Compounds and compositions for inhibition of FASN

ABSTRACT

The present invention relates to compounds and composition for inhibition of FASN, their synthesis, applications, and antidotes. An illustrative compound of the invention is shown below:

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/119,962, filed Aug. 31, 2018, which is a continuation of U.S. patentapplication Ser. No. 14/775,877, filed Sep. 14, 2015, which is the U.S.national phase of International Application No. PCT/US2014/023388, filedMar. 11, 2014, which claims the benefit of U.S. Provisional ApplicationNo. 61/779,908, filed Mar. 13, 2013, and U.S. Provisional ApplicationNo. 61/779,962, filed Mar. 13, 2013, all of which are incorporated byreference in their entirety.

FIELD OF THE INVENTION

The present invention relates to compounds and compositions forinhibition of fatty acid synthase (“FASN”), their synthesis,applications and antidote.

BACKGROUND OF THE INVENTION

Fatty acid synthase (hereinafter “FASN;” also known as “FAS”) playsfundamental roles in both cellular metabolism and cellular signaling.FASN catalyzes the formation of long-chain fatty acids from acetyl-CoA,malonyl-CoA and nicotinamide adenine dinucleotide phosphate (NADPH),thus getting involved in energy production and storage, cellularstructure and formation of intermediates in the biosynthesis of hormonesand other biologically important molecules.

Extensive research has been conducted to study the expression, function,and regulation of both FASN encoding genes and the various forms of FASNproteins. Several studies indicate that FASN is involved in theoncogenesis and tumor progression of various cancers. For example, FASNgene amplification and protein overexpression was observed in humanbreast cancer cell lines. (Hunt D A, Lane H M, Zygmont M E, Dervan P A,Hennigar R A (2007), MRNA stability and overexpression of fatty acidsynthase in human breast cancer cell lines. Anticancer Res. 27 (1A):27-34; Kuhaja F P, (2006) Fatty acid synthase and cancer: Newapplication of an old pathway. Cancer Research, 66(12) 5977-5980;Menendez J A, Lupu R (2007) Fatty acid synthase and the lipogenicphenotype in cancer pathogenesis. Nature Review Cancer, 7, 763-777.) Inaddition, a study focusing on ovarian neoplasms revealed that elevatedlevels of FASN serve as an indicator for shorter survival of thesubject. (Gansler T S, Hardman W, Hunt D A, Schaffel S, Hennigar R A(June 1997). Increased expression of fatty acid synthase (OA-519) inovarian neoplasms predicts shorter survival. Hum. Pathol. 28 (6):686-92). In summary, correlation of elevated FASN expression or activitywith high tumor grade and advanced stage in primary breast, prostate,and colorectal cancers has drawn attention to the enzyme as a possibledrug target and marker of poor prognosis.

In addition to the involvement in oncogenesis, FASN has also beenidentified as a factor that may influence the progression of diseasessuch as diabetes and uterine leiomyomata. In particular, one study foundthat a FASN inhibitor, platensimycin, reduced ambient glucose levels inmouse models of diabetes. Furthermore, FASN inhibitors have been shownto be potentially effective in inducing weight loss (e.g EP0869784-A).Similarly, a genome-wide study suggests that FASN may contribute to thepredisposition to uterine leiomyomata.

Furthermore, FASN has been identified as a target for treatment ofmicrobial infections. In particular, fatty acid synthesis or the levelof fatty acid has been reported to be critical in viral pathogenesis. Inaddition, FASN has been implicated in pathogeneiss of human cytomegalovirus (HCMV), influenza A viruses and Hepatitis C (See, e.g., Munger etal., Nature Biotechnology, 26: 1179-1186 (2008)). It has also beenreported that the FASN expression is increased in the cells infected bycoxsackievirus B3 (CVB3), a picornavirus, and the replication of CVB3 isblocked by FASN inhibitors. (See Rassmann et al., Antiviral Research,76: 150-158 (2007)). In addition, FASN has been reported to be importantin lytic viral replication of Epstein-Barr virus (EBV). (Li et al.,Journal of Virology, 78(8): 4197-4206 (2004)). FASN has also beenimplicated to have a role in the replication of dengue virus (See, e.g.,Heaton et al., Proc. Natl. Acad. Sci., 107(40): 17345-17350 (2010); andSamsa et al., PLoS Pathegens, 5(10): e1000632 (2009)). Moreover, FASNplays important role in HCV infection by controlling viral entry andproduction (Yang W, Hood B L, Chadwick S L, Watkins, Luo G, Conrads T P,Wang T (2008), Fatty acid synthase is up-regulated during hepatitis Cvirus infection and regulates hepatitis C virus entry and production.Hepatology, 48, 13967-1403)

Significant efforts have been focusing on generating FASN inhibitorsthat may help to provide a treatment for cancer and other relateddiseases. A number of inhibitor families have been identified andpublished, such as the azabenzimidazoles series (WO 2011/066211 andrelated publications) and the sulfonamide derivatives series (WO2008/075070 and related publications) from AstraZeneca UK Ltd. However,due to FASN's importance and the shortcomings in the publishedcompounds, there is still an unmet need for potent and highly specificFASN inhibitors.

The current invention introduces a new set of compounds that selectivelyinhibits FASN activities and modulates the growth and proliferation ofcancer cell lines. The synthetic processes of the new compounds are alsoincluded. These compounds may have significant pharmaceuticalimplications in the treatment of cancer, as well as other diseases suchas viral infections, obesity, and diabetes.

SUMMARY OF THE INVENTION

One aspect of this invention is the provision of compounds,compositions, and kits for FASN inhibition comprising a compound offormula I:

wherein

-   R₁ is a C₁-C₃ hydroxyl-alkyl either unsubstituted or substituted    with —CH₃ or —CH_(z)F_(3-z), 5 membered cycloalkyl either    unsubstituted or substituted with substituents selected from the    group consisting of deuterium, —R_(p), —OR_(p), —NHR_(p), and    —NR_(p)R_(p1),    -   or 3 or 4 membered cycloalkyl or heterocycloalkyl wherein (i)        the heteroatom ring member of the 3 or 4 membered        heterocycloalkyl is independently selected from O, S, or N,        and (ii) each of said 3 or 4 membered cycloalkyl or        heterocycloalkyl is either unsubstituted or optionally        substituted with substituents selected from the group consisting        of deuterium, —R_(a), —OR_(a), —NHR_(a), and —NR_(a)R_(a1);-   L is a 5-10 membered monocyclic or bicyclic alkyl or heteroalkyl    wherein (i) the heteroatom ring members of the 5-10 membered    monocyclic or bicyclic heteroalkyl are independently selected from    O, S, or N, and (ii) each of the 5-10 membered monocyclic or    bicyclic alkyl or heteroalkyl is either unsubstituted or optionally    substituted with substituents selected from the group consisting of    deuterium and —R_(b);-   A and B are independently O or S;-   Ar₁ is a 4-10 membered monocyclic or bicyclic aryl, heteroaryl or    heterocycloalkyl, wherein (i) said 4-10 membered monocyclic or    bicyclic heteroaryl or heterocycloalkyl have 1, 2, 3, or 4    heteroatoms which are independently selected from N, S or O,    and (ii) each of said 4-10 membered monocyclic or bicyclic aryl,    heteroaryl, or heterocycloalkyl is either unsubstituted or    optionally independently substituted with 1 or more substituents    which can be the same or different and are independently selected    from the group consisting of deuterium, halo, alkyl, —CH_(z)F_(3-z),    cyano, hydroxyl, hydroxylalkyl, amino, aminoalkyl-, (amino)alkoxy-,    —CONH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl),    —C(O)N(aryl)₂, —OCH_(z)F_(3-z), -alkyl, -alkenyl, -alkynyl, -alkoxy    or (alkoxyalkyl)amino-, —N(R_(c))—C(O)-alkyl, —N(R_(c))—C(O)-aryl,    -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the    proviso that no two adjacent ring heteroatoms are both S or both O;-   R₂ is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered    monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl    has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently    selected from N, S or O, and (ii) wherein each of said aryl,    heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted    or optionally substituted with 1 or more substituents which can be    the same or different and are independently selected from the group    consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-,    hydroxylcycoalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-,    hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH₂,    —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl, alkoxy-, -alkenyl,    -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl,    -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl,    —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl),    —O(heteroaryl), ONH₂, —C(O)NH(alkyl), —C(O)N(aryl)₂,    —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO₂), —NH(SO₂)alkyl,    —NH(SO₂)aryl, —NH(SO₂)heteroaryl, —N(SO₂)cycolalkyl, —C(O)N(alkyl)₂,    (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O)₂-alkyl,    —S(O)₂-aryl, —S(O)₂-cycloalkyl, —C(O)N(alkyl)₂, —C(O)alkyl,    —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl,    NH—C(O)-heterocycloalkyl-R_(d), —NH—C(O)— R_(d)—(O)alkyl,    —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl,    NH₂(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl,    NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R_(d))—C(O)-alkyl,    —NH(R_(d))—C(O)-aryl, —NH(R_(d))—S(O₂)cycloalkyl, —S(O₂)NH₂,    —S(O₂)NH(alkyl), —S(O₂)N(R_(d))cycloalkyl, —S(O₂)N(alkyl)₂,    —C(O)N(H)(alkyl), —C(O)N(R_(d)) (cycloalkyl), methylenedioxy,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), and -alkoxy;-   R_(p) and R_(p1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(a) and R_(a1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(b) is H, halo, C₁-C₄ alkyl, C₁-C₃ hydroxyl-alkyl, or C₃-C₄    cycloalkyl;-   R_(c) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   R_(d) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   and z is 0, 1 or 2;-   and pharmaceutically acceptable salts, solvates, esters, prodrugs    and isomers thereof.

Another aspect of this invention is the provision of compounds,compositions, and kits for FASN inhibition comprising a compound offormula I-A:

wherein:

-   R₁ is a C₁-C₃ hydroxyl-alkyl either unsubstituted or substituted    with —CH₃ or —CH_(z)F_(3-z), 5-membered cycloalkyl either    unsubstituted or substituted with substituents selected from the    group consisting of deuterium, —R_(p), —OR_(p), —NHR_(p), and    —NR_(p)R_(p1),    -   or 3 or 4 membered cycloalkyl or heterocycloalkyl wherein (i)        the heteroatom ring member of the 3 or 4 membered        heterocycloalkyl is independently selected from O, S, or N,        and (ii) each of said 3 or 4 membered cycloalkyl or        heterocycloalkyl is either unsubstituted or optionally        substituted with substituents selected from the group consisting        of deuterium, —R_(a), —OR_(a), —NHR_(a), and —NR_(a)R_(a1);-   Ar₁ is a 4-10 membered monocyclic or bicyclic aryl, heteroaryl or    heterocycloalkyl, wherein (i) said 4-10 membered monocyclic or    bicyclic heteroaryl or heterocycloalkyl have 1, 2, 3, or 4    heteroatoms which are independently selected from N, S or O,    and (ii) each of said 4-10 membered monocyclic or bicyclic aryl,    heteroaryl, or heterocycloalkyl is either unsubstituted or    optionally independently substituted with 1 or more substituents    which can be the same or different and are independently selected    from the group consisting of deuterium, halo, alkyl, —CH_(z)F_(3-z),    cyano, hydroxyl, hydroxylalkyl, amino, aminoalkyl-, (amino)alkoxy-,    —CONH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl),    —C(O)N(aryl)₂, —OCH_(z)F_(3-z), -alkyl, -alkenyl, -alkynyl, -alkoxy    or (alkoxyalkyl)amino-, —N(R_(c))—C(O)-alkyl, —N(R_(c))—C(O)-aryl,    -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the    proviso that no two adjacent ring heteroatoms are both S or both O;-   R₂ is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered    monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl    has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently    selected from N, S or O, and (ii) wherein each of said aryl,    heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted    or optionally substituted with 1 or more substituents which can be    the same or different and are independently selected from the group    consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-,    hydroxylcycoalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-,    hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH₂,    —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl, alkoxy-, -alkenyl,    -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl,    -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl,    —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl),    —O(heteroaryl), ONH₂, —C(O)NH(alkyl), —C(O)N(aryl)₂,    —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO₂), —NH(SO₂)alkyl,    —NH(SO₂)aryl, —NH(SO₂)heteroaryl, —N(SO₂)cycolalkyl, —C(O)N(alkyl)₂,    (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O)₂-alkyl,    —S(O)₂-aryl, —S(O)₂-cycloalkyl, —C(O)N(alkyl)₂, —C(O)alkyl,    —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl,    NH—C(O)-heterocycloalkyl-R_(d), —NH—C(O)— R_(d)—(O)alkyl,    —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl,    NH₂(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl,    NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R_(d))—C(O)-alkyl,    —NH(R_(d))—C(O)-aryl, —NH(R_(d))—S(O₂)cycloalkyl, —S(O₂)NH₂,    —S(O₂)NH(alkyl), —S(O₂)N(R_(d))cycloalkyl, —S(O₂)N(alkyl)₂,    —C(O)N(H)(alkyl), —C(O)N(R_(d))(cycloalkyl), methylenedioxy,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), and -alkoxy;-   R_(p) and R_(p1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(a) and R_(a1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(c) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   R_(d) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   and z is 0, 1 or 2;-   and pharmaceutically acceptable salts, solvates, esters, prodrugs    and isomers thereof.

Another aspect of this invention is the provision of compounds,compositions, and kits for FASN inhibition comprising a compound offormula I-B:

wherein:

-   Ar₁ is a 4-10 membered monocyclic or bicyclic aryl, heteroaryl or    heterocycloalkyl, wherein (i) said 4-10 membered monocyclic or    bicyclic heteroaryl or heterocycloalkyl have 1, 2, 3, or 4    heteroatoms which are independently selected from N, S or O,    and (ii) each of said 4-10 membered monocyclic or bicyclic aryl,    heteroaryl, or heterocycloalkyl is either unsubstituted or    optionally independently substituted with 1 or more substituents    which can be the same or different and are independently selected    from the group consisting of deuterium, halo, alkyl, —CH_(z)F_(3-z),    cyano, hydroxyl, hydroxylalkyl, amino, aminoalkyl-, (amino)alkoxy-,    —CONH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl),    —C(O)N(aryl)₂, —OCH_(z)F_(3-z), -alkyl, -alkenyl, -alkynyl, -alkoxy    or (alkoxyalkyl)amino-, —N(R_(c))—C(O)-alkyl, —N(R_(c))—C(O)-aryl,    -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the    proviso that no two adjacent ring heteroatoms are both S or both O;    R₂ is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered    monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl    has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently    selected from N, S or O, and (ii) wherein each of said aryl,    heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted    or optionally substituted with 1 or more substituents which can be    the same or different and are independently selected from the group    consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-,    hydroxylcycoalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-,    hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH₂,    —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl, alkoxy-, -alkenyl,    -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl,    -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl,    —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl),    —O(heteroaryl), ONH₂, —C(O)NH(alkyl), —C(O)N(aryl)₂,    —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO₂), —NH(SO₂)alkyl,    —NH(SO₂)aryl, —NH(SO₂)heteroaryl, —N(SO₂)cycolalkyl, —C(O)N(alkyl)₂,    (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O)₂-alkyl,    —S(O)₂-aryl, —S(O)₂-cycloalkyl, —C(O)N(alkyl)₂, —C(O)alkyl,    —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl,    NH—C(O)-heterocycloalkyl-R_(d), —NH—C(O)— R_(d)—(O)alkyl,    —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl,    NH₂(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl,    NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R_(d))—C(O)-alkyl,    —NH(R_(d))—C(O)-aryl, —NH(R_(d))—S(O₂)cycloalkyl, —S(O₂)NH₂,    —S(O₂)NH(alkyl), —S(O₂)N(R_(d))cycloalkyl, —S(O₂)N(alkyl)₂,    —C(O)N(H)(alkyl), —C(O)N(R_(d)) (cycloalkyl), methylenedioxy,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), and -alkoxy;-   R_(c) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   R_(d) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   and z is 0, 1 or 2;-   and pharmaceutically acceptable salts, solvates, esters, prodrugs    and isomers thereof.

Another aspect of this invention is the provision of compounds,compositions, and kits for FASN inhibition comprising a compound offormula I-C:

wherein:

-   R₁ is a C₁-C₃ hydroxyl-alkyl either unsubstituted or substituted    with —CH₃ or —CH_(z)F_(3-z), 5 membered cycloalkyl either    unsubstituted or substituted with substituents selected from the    group consisting of deuterium, —R_(p), —OR_(p), —NHR_(p), and    —NR_(p)R_(p1),    -   or 3 or 4 membered cycloalkyl or heterocycloalkyl wherein (i)        the heteroatom ring member of the 3 or 4 membered        heterocycloalkyl is independently selected from O, S, or N,        and (ii) each of said 3 or 4 membered cycloalkyl or        heterocycloalkyl is either unsubstituted or optionally        substituted with substituents selected from the group consisting        of deuterium, —R_(a), —OR_(a), —NHR_(a), and —NR_(a)R_(a1);-   R₂ is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered    monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl    has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently    selected from N, S or O, and (ii) wherein each of said aryl,    heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted    or optionally substituted with 1 or more substituents which can be    the same or different and are independently selected from the group    consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-,    hydroxylcycoalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-,    hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH₂,    —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl, alkoxy-, -alkenyl,    -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl,    -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl,    —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl),    —O(heteroaryl), ONH₂, —C(O)NH(alkyl), —C(O)N(aryl)₂,    —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO₂), —NH(SO₂)alkyl,    —NH(SO₂)aryl, —NH(SO₂)heteroaryl, —N(SO₂)cycolalkyl, —C(O)N(alkyl)₂,    (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O)₂-alkyl,    —S(O)₂-aryl, —S(O)₂-cycloalkyl, —C(O)N(alkyl)₂, —C(O)alkyl,    —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl,    NH—C(O)-heterocycloalkyl-R_(d), —NH—C(O)— R_(d)—(O)alkyl,    —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl,    NH₂(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl,    NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R_(d))—C(O)-alkyl,    —NH(R_(d))—C(O)-aryl, —NH(R_(d))—S(O₂)cycloalkyl, —S(O₂)NH₂,    —S(O₂)NH(alkyl), —S(O₂)N(R_(d))cycloalkyl, —S(O₂)N(alkyl)₂,    —C(O)N(H)(alkyl), —C(O)N(R_(d)) (cycloalkyl), methylenedioxy,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), and -alkoxy;-   R_(p) and R_(p1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(a) and R_(a1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(d) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   R_(q) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   and z is 0, 1 or 2;-   and pharmaceutically acceptable salts, solvates, esters, prodrugs    and isomers thereof.

Another aspect of this invention is the provision of compounds,compositions, and kits for FASN inhibition comprising a compound offormula I-D:

wherein:

-   -   (I-D)

-   wherein:

-   R₁′ is OH or NH₂;

-   R₂ is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered    monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl    has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently    selected from N, S or O, and (ii) wherein each of said aryl,    heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted    or optionally substituted with 1 or more substituents which can be    the same or different and are independently selected from the group    consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-,    hydroxylcycoalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-,    hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH₂,    —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl, alkoxy-, -alkenyl,    -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl,    -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl,    —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl),    —O(heteroaryl), ONH₂, —C(O)NH(alkyl), —C(O)N(aryl)₂,    —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO₂), —NH(SO₂)alkyl,    —NH(SO₂)aryl, —NH(SO₂)heteroaryl, —N(SO₂)cycolalkyl, —C(O)N(alkyl)₂,    (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O)₂-alkyl,    —S(O)₂-aryl, —S(O)₂-cycloalkyl, —C(O)N(alkyl)₂, —C(O)alkyl,    —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl,    NH—C(O)-heterocycloalkyl-R_(d), —NH—C(O)— R_(d)—(O)alkyl,    —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl,    NH₂(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl,    NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R_(d))—C(O)-alkyl,    —NH(R_(d))—C(O)-aryl, —NH(R_(d))—S(O₂)cycloalkyl, —S(O₂)NH₂,    —S(O₂)NH(alkyl), —S(O₂)N(R_(d))cycloalkyl, —S(O₂)N(alkyl)₂,    —C(O)N(H)(alkyl), —C(O)N(R_(d)) (cycloalkyl), methylenedioxy,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), and -alkoxy;

-   R_(d) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;

-   and z is 0, 1 or 2;

-   and pharmaceutically acceptable salts, solvates, esters, prodrugs    and isomers thereof.

Another aspect of this invention is the provision of methods of treatinga disease via the inhibition of FASN in a subject (e.g., a human) inneed thereof by administering to the subject an effective amount of thecompound or the pharmaceutical formulation of the present invention.

Another preferred embodiment is a pharmaceutical formulation comprisinga pharmaceutically acceptable compound of the present invention, whichprovides, upon administration to a human, a decrease in tumor burdenand/or metastases. The pharmaceutical formulation can be administered byoral means or other suitable means. e.g., intravenously or by injection.

Yet another embodiment is a method of treating ovarian cancer in asubject (e.g., a human) in need thereof by administering to the subjecta therapeutically effective amount of the compound or the pharmaceuticalformulation of the present invention.

Yet another embodiment is a method of treating colon cancer in a subject(e.g., a human) in need thereof by administering to the subject aneffective amount of the compound or the pharmaceutical formulation ofthe present invention.

Yet another embodiment is a method of treating breast cancer in asubject (e.g., a human) in need thereof by administering to the subjectan effective amount of the pharmaceutical formulation of the presentinvention.

Yet another embodiment is a method of treating leukemia in a subject(e.g., a human) in need thereof by administering to the subject aneffective amount of the compound or the pharmaceutical formulation ofthe present invention.

Yet another embodiment is a method of treating colon cancer, before orafter surgical resection and/or radiation therapy, in a subject (e.g., ahuman) in need thereof by administering to the subject an effectiveamount of the compound or the pharmaceutical formulation of the presentinvention.

Yet another embodiment is a method of treating cancer, before or aftersurgical resection and/or radiation therapy, in a subject (e.g., ahuman) in need thereof by administering to the subject an effectiveamount of the compound or the pharmaceutical formulation of the presentinvention, including adjunctive therapy to treat nausea, with or withoutdexamethasone.

Yet another embodiment is a method of treating cancer, before or aftersurgical resection and or radiation therapy, in a subject (e.g., ahuman) in need thereof by administering to the subject an effectiveamount of the compound or the pharmaceutical formulation of the presentinvention, including adjunctive therapy with one or more additionaltherapeutic agents, or their pharmaceutically acceptable salts thereof.Non-limiting examples of such additional therapeutic agents includecytotoxic agents (such as for example, but not limited to, DNAinteractive agents (such as cisplatin or doxorubicin)); taxanes (e.g.taxotere, taxol); topoisomerase II inhibitors (such as etoposide);topoisomerase I inhibitors (such as irinotecan (or CPT-11), camptostar,or topotecan); tubulin interacting agents (such as paclitaxel, docetaxelor the epothilones); hormonal agents (such as tamoxifen); thymidilatesynthase inhibitors (such as 5-fluorouracil or 5-FU); anti-metabolites(such as methoxtrexate); alkylating agents (such as temozolomide,cyclophosphamide); Farnesyl protein transferase inhibitors (such as,SARASAR™.(4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,-6]cyclohepta[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoehtyl]-1-piperidine-carboxamide,or SCH 66336), tipifarnib (Zarnestra® or R115777 from JanssenPharmaceuticals), L778,123 (a farnesyl protein transferase inhibitorfrom Merck & Company, Whitehouse Station, N.J.), BMS 214662 (a farnesylprotein transferase inhibitor from Bristol-Myers Squibb Pharmaceuticals,Princeton, N.J.); signal transduction inhibitors (such as, Iressa® (fromAstra Zeneca Pharmaceuticals, England), Tarceva® (EGFR kinaseinhibitors), antibodies to EGFR (e.g., C225), GLEEVEC® (C-abl kinaseinhibitor from Novartis Pharmaceuticals, East Hanover, N.J.);interferons such as, for example, Intron® (from Merck & Company),Peg-Intron® (from Merck & Company); hormonal therapy combinations;aromatase combinations; ara-C, adriamycin, cytoxan, and gemcitabine.

Other anti-cancer (also known as anti-neoplastic) agents include but arenot limited to Uracil mustard, Chlormethine, Ifosfamide, Melphalan,Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,oxaliplatin (ELOXATIN®. from Sanofi-Synthelabo Pharmaceuticals, France),Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, Herceptin, Bexxar, Velcade®, Zevalin,Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,Ifosfomide, Rituximab, C225, and Campath, 5-fluorouracil and leucovorin,with or without a 5-HT₃ receptor inhibitor (e.g., dolansetron,granisetron, ondansetron) with or without dexamethasone.

Yet another embodiment is a method of treating diabetes in a subject(e.g., a human) in need thereof by administering to the subject aneffective amount of the compound or the pharmaceutical formulation ofthe present invention.

Yet another embodiment is a method of treating obesity or over weight ina subject (e.g., a human) in need thereof by administering to thesubject an effective amount of the compound or the pharmaceuticalformulation of the present invention.

Yet another embodiment is a method of treating uterine leiomyomata in asubject (e.g., a human) in need thereof by administering to the subjectan effective amount of the compound or the pharmaceutical formulation ofthe present invention.

Yet another embodiment is a method of treating microbial infections in asubject (e.g., a human) in need thereof by administering to the subjectan effective amount of the compound or the pharmaceutical formulation ofthe present invention.

Yet another embodiment is a method of treating viral infections,including but not limited to infections caused by HCMV, influenzaA-virus, Hepatis C-virus, CVB3, picorna virus, EBC and dengue virus in asubject (e.g., a human) in need thereof by administering to the subjectan effective amount of the compound or the pharmaceutical formulation ofthe present invention.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein (oras known to those skilled in the art) and the other pharmaceuticallyactive agent or treatment within its dosage range. For example, the CDC2inhibitor olomucine has been found to act synergistically with knowncytotoxic agents in inducing apoptosis (J. Cell Sci., (1995) 108, 2897).The compounds of the invention may also be administered sequentiallywith known anticancer or cytotoxic agents when a combination formulationis inappropriate. In any combination treatment, the invention is notlimited in the sequence of administration; compounds of the Formulas maybe administered either prior to or after administration of the knownanticancer or cytotoxic agent. For example, the cytotoxic activity ofthe cyclin-dependent kinase inhibitor flavopiridol is affected by thesequence of administration with anticancer agents. Cancer Research,(1997) 57, 3375. Such techniques are within the skills of personsskilled in the art as well as attending physicians.

Any of the aforementioned methods may be augmented by administration offluids (such as water), loop diuretics, one or more of achemotherapeutic or antineoplastic agent, such as leucovorin andfluorouracil, and an adjunctive chemotherapeutic agent (such asfilgrastim and erythropoietin), or any combination of the foregoing.

Yet another embodiment is a method for administering a compound of theinstant invention to a subject (e.g., a human) in need thereof byadministering to the subject the pharmaceutical formulation of thepresent invention.

Yet another embodiment is a method of preparing a pharmaceuticalformulation of the present invention by mixing at least onepharmaceutically acceptable compound of the present invention, and,optionally, one or more pharmaceutically acceptable additives orexcipients.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18th Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally or intravenously.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 1000 mg, preferably fromabout 1 mg to about 500 mg, more preferably from about 1 mg to about 250mg, still more preferably from about 1 mg to about 25 mg, according tothe particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two tofour divided doses.

Definitions

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings. If a definition is missing, convention definition as known toone skilled in the art controls.

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

The term “FASN” refers all classes, types, subtypes, isotypes, segments,variants, and mutant forms of fatty acid synthase.

The term “inhibitor” refers to a molecule such as a compound, a drug, anenzyme activator or a hormone that blocks or otherwise interferes with aparticular biological activity.

The terms “effective amount” or “therapeutically effective amount” referto a sufficient amount of the agent to provide the desired biologicalresult. That result can be reduction and/or alleviation of the signs,symptoms, or causes of a disease, or any other desired alteration of abiological system. For example, an “effective amount” for therapeuticuse is the amount of the composition comprising a compound as disclosedherein required to provide a clinically significant decrease in adisease. An appropriate “effective” amount in any individual case may bedetermined by one of ordinary skill in the art using routineexperimentation. Thus, the expression “effective amount” generallyrefers to the quantity for which the active substance has therapeuticeffects. In the present case the active substance is the inhibitor ofthe fatty acid synthase (FASN).

As used herein, the terms “treat” or “treatment” are synonymous with theterm “prevent” and are meant to indicate a postponement of developmentof diseases, preventing the development of diseases, and/or reducingseverity of such symptoms that will or are expected to develop. Thus,these terms include ameliorating existing disease symptoms, preventingadditional symptoms, ameliorating or preventing the underlying metaboliccauses of symptoms, inhibiting the disorder or disease, e.g., arrestingthe development of the disorder or disease, relieving the disorder ordisease, causing regression of the disorder or disease, relieving acondition caused by the disease or disorder, or stopping or alleviatingthe symptoms of the disease or disorder.

By “pharmaceutically acceptable” or “pharmacologically acceptable” ismeant a material which is not biologically or otherwise undesirable—thematerial may be administered to an individual without causing anyundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

“Carrier materials” or what are also referred to as “excipients” includeany commonly used excipients in pharmaceutics and should be selected onthe basis of compatibility and the release profile properties of thedesired dosage form. Exemplary carrier materials include, e.g., binders,suspending agents, disintegration agents, filling agents, surfactants,solubilizers, stabilizers, lubricants, wetting agents, diluents, and thelike. “Pharmaceutically compatible carrier materials” may comprise,e.g., acacia, gelatin, colloidal silicon dioxide, calciumglycerophosphate, calcium lactate, maltodextrin, glycerine, magnesiumsilicate, sodium caseinate, soy lecithin, sodium chloride, tricalciumphosphate, dipotassium phosphate, sodium stearoyl lactylate,carrageenan, monoglyceride, diglyceride, pregelatinized starch, and thelike. See, e.g., Hoover, John E., Remington's Pharmaceutical Sciences,Mack Publishing Co., Easton, Pa. 1975.

As used herein, the term “subject” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the presentinvention, the mammal is a human.

As used herein, “alkyl” means a straight chain or branched saturatedchain having from 1 to 10 carbon atoms. Representative saturated alkylgroups include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the like,and longer alkyl groups, such as heptyl, and octyl and the like. Analkyl group can be unsubstituted or substituted. Alkyl groups containingthree or more carbon atoms may be straight, branched or cyclized. Asused herein, “lower alkyl” means an alkyl having from 1 to 6 carbonatoms.

As used herein, an “alkenyl” includes an unbranched or branchedhydrocarbon chain having one or more double bonds therein. The doublebond of an alkenyl group can be unconjugated or conjugated to anotherunsaturated group. Illustrative alkenyl groups include, but are notlimited to, (C₂-C₈) alkenyl groups, such as ethylenyl, vinyl, allyl,butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl,2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl andthe like. An alkenyl group can be unsubstituted or substituted.

As used herein, “alkynyl” includes an unbranched or branched hydrocarbonchain having one or more triple bonds therein. The triple bond of analkynyl group can be unconjugated or conjugated to another unsaturatedgroup. Suitable alkynyl groups include, but are not limited to, (C₂-C₆)alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl,methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl,4-butyl-2-hexynyl and the like. An alkynyl group can be unsubstituted orsubstituted.

The terms “trifluoromethyl,” “sulfonyl,” and “carboxyl” include CF₃,SO₂, and CO₂H, respectively.

The term “hydroxyl” means an OH group;

The term alkyl hydroxyl or hydroxyalkyl means an alkyl group as definedabove, where the alkyl group has an OH group disposed thereon.

The term “alkoxy” as used herein includes —O-(alkyl), wherein alkyl isdefined above.

The term “aminoalkyl” as used herein means a group having one or morenitrogen atoms and one or more alkyl groups as defined above on thenitrogen.

“Aralkyl” or “arylalkyl” means an aryl-alkyl-group in which the aryl andalkyl are as previously described. Preferred aralkyls comprise a loweralkyl group. Non-limiting examples of suitable aralkyl groups includebenzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parentmoiety is through the alkyl.

“Heteroarylalkyl” means a heteroaryl moiety as defined herein linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl andthe like.

“Heterocyclylalkyl” means a heterocyclyl moiety as defined herein linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable heterocyclylalkyls include piperidinylmethyl,piperazinylmethyl and the like.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in the Formulas, its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The term “deuterium” as used herein means a stable isotope of hydrogenhaving odd numbers of protons and neutrons.

The term “halo” as used herein means a substituent having at least onehalogen selected from fluorine, chlorine, bromine, and iodine.

The term “cyano” as used herein means a substituent having a carbon atomjoined to a nitrogen atom by a triple bond.

The term “amino” as used herein means a substituent containing at leastone nitrogen atom.

The term “(amino)alkoxy” as used herein means a substituent having atleast one amino group and at least one alkoxy group.

The term “aryloxy” as used herein means a substituent of the form Ar—O—where Ar is an aryl group as defined herein.

The term “methylenedioxy” as used herein means a functional group withthe structural formula —O—CH₂—O— which is connected to the molecule bytwo chemical bonds via the oxygens.

As used herein, “alkoxyalkyl” means -(alkyl)-O-(alkyl), wherein each“alkyl” is independently an alkyl group defined above.

The term “(alkoxyalkyl)amino” as used herein means a substituent havingat least one alkoxyalkyl group as defined above and at least one aminogroup as defined above.

As used herein, the term “aryl” refers to a monocyclic, or fusedpolycyclic, aromatic carbocycle (ring structure having ring atoms thatare all carbon) having from 3 to 24 ring atoms per ring. Illustrativeexamples of aryl groups include, but are not limited to, the followingmoieties:

and the like.

Illustrative substituted aryls include:

and the like.

As used herein, the term “heteroaryl” refers to a monocyclic, or fusedpolycyclic, aromatic heterocycle (ring structure having ring atomsselected from carbon atoms as well as nitrogen, oxygen, and sulfurheteroatoms) having from 3 to 24 ring atoms per ring. Illustrativeexamples of heteroaryl and substituted heteroaryl groups include, butare not limited to the following moieties:

and the like.

As used herein, the term “cycloalkyl” refers to a saturated or partiallysaturated, monocyclic or fused or spiro polycyclic, carbocycle havingfrom 3 to 24 ring atoms per ring. Illustrative examples of cycloalkylgroups include, but are not limited to, the following moieties:

and the like.

As used herein, the term “heterocycloalkyl” refers to a monocyclic, orfused or spiro, polycyclic, ring structure that is saturated orpartially saturated and has from 3 to 24 ring atoms per ring selectedfrom C atoms and N, O, and S heteroatoms. Illustrative examples ofheterocycloalkyl and substituted heterocycloalkyl groups include, butare not limited to:

and the like.

Numerical ranges, as used herein, are intended to include sequentialintegers. For example, a range expressed as “from 0 to 4” would include0, 1, 2, 3 and 4.

As used herein, the terms “monocyclic, bicyclic, or tricyclic aryl,heteroaryl, cycloalkyl, or heterocycloalkyl,” mean any ring of abicyclic or tricyclic structure may independently be aryl, heteroaryl,cycloalkyl, or heterocycloalkyl in an ortho or ortho and peri fusedsystem.

As used herein, the term “substituted” means that the specified group ormoiety bears one or more suitable substituents wherein the substituentsmay connect to the specified group or moiety at one or more positions.For example, an aryl substituted with a cycloalkyl may indicate that thecycloalkyl connects to one atom of the aryl with a bond or by fusingwith the aryl and sharing two or more common atoms.

As used herein, the term “unsubstituted” means that the specified groupbears no substituents.

As used herein, the term “optionally substituted” means that thespecified group is unsubstituted or substituted by one or moresubstituents.

When a multifunctional moiety is shown, the point of attachment to thecore may be identified by a line. For e.g. (cycloalkyloxy)alkyl- refersto alkyl being the point of attachment to the core while cycloalkyl isattached to alkyl via the oxy group. In the absence of a line,attachment at any position may be assumed.

The expression “adjunctive chemotherapeutic agent” generally refers toagents which treat, alleviate, relieve, or ameliorate the side effectsof chemotherapeutic agents. Such agents include those which modify bloodcell growth and maturation. Examples of adjunctive chemotherapeuticagents include, but are not limited to, filgrastim and erythropoietin.Other such adjunctive chemotherapeutic agents include those whichinhibit nausea associated with administration of the chemotherapeuticagents, such as a 5-HT₃ receptor inhibitor (e.g., dolansetron,granisetron, or ondansetron), with or without dexamethasone.

The terms “chemotherapeutic agent” and “antineoplastic agent” generallyrefer to agents which treat, prevent, cure, heal, alleviate, relieve,alter, remedy, ameliorate, improve, or affect malignancies and theirmetastasis. Examples of such agents (also known as “antineoplasticagents”) include, but are not limited to, prednisone, fluorouracil(e.g., 5-fluorouracil (5-FU)), anastrozole, bicalutamide, carboplatin,cisplatin, chlorambucil, cisplatin, carboplatin, docetaxel, doxorubicin,flutamide, interferon-alpha, letrozole, leuprolide, megestrol,mitomycin, oxaliplatin, paclitaxel, plicamycin (Mithracin™), tamoxifen,thiotepa, topotecan, valrubicin, vinblastine, vincristine, and anycombination of any of the foregoing. Additional such agents aredescribed later.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise.

When used as a therapeutic agent the inhibitors of the FASN (FASN)described herein may be administered with one or more physiologicallyacceptable excipients. A physiologically acceptable carrier or excipientis a formulation to which the compound can be added to dissolve it orotherwise facilitate its administration.

The dosage forms of the present invention, may contain a mixture of oneor more compounds of this invention, and may include additionalmaterials known to those skilled in the art as pharmaceuticalexcipients. Stabilizing additives may be incorporated into the deliveryagent solution. With some drugs, the presence of such additives promotesthe stability and dispersibility of the agent in solution. Thestabilizing additives may be employed at a concentration ranging fromabout 0.1 and 5% (W/V), preferably about 0.5% (W/V). Suitable, butnon-limiting, examples of stabilizing additives include gum acacia,gelatin, methyl cellulose, polyethylene glycol, carboxylic acids andsalts thereof, and polylysine. The preferred stabilizing additives aregum acacia, gelatin and methyl cellulose.

Acidifying agents (acetic acid, glacial acetic acid, citric acid,fumaric acid, hydrochloric acid, diluted hydrochloric acid, malic acid,nitric acid, phosphoric acid, diluted phosphoric acid, sulfuric acid,tartaric acid); Aerosol propellants (butane, dichlorodifluoro-methane,dichlorotetrafluoroethane, isobutane, propane,trichloromonofluoromethane); Air displacements (carbon dioxide,nitrogen); Alcohol denaturants (denatonium benzoate, methyl isobutylketone, sucrose octacetate); Alkalizing agents (strong ammonia solution,ammonium carbonate, diethanolamine, diisopropanolamine, potassiumhydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodiumhydroxide, trolamine); Anticaking agents (see glidant); Antifoamingagents (dimethicone, simethicone); Antimicrobial preservatives(benzalkonium chloride, benzalkonium chloride solution, benzelthoniumchloride, benzoic acid, benzyl alcohol, butylparaben, cetylpyridiniumchloride, chlorobutanol, chlorocresol, cresol, dehydroacetic acid,ethylparaben, methylparaben, methylparaben sodium, phenol, phenylethylalcohol, phenylmercuric acetate, phenylmercuric nitrate, potassiumbenzoate, potassium sorbate, propylparaben, propylparaben sodium, sodiumbenzoate, sodium dehydroacetate, sodium propionate, sorbic acid,thimerosal, thymol); Antioxidants (ascorbic acid, acorbyl palmitate,butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorousacid, monothioglycerol, propyl gallate, sodium formaldehyde sulfoxylate,sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol,tocopherols excipient); Buffering agents (acetic acid, ammoniumcarbonate, ammonium phosphate, boric acid, citric acid, lactic acid,phosphoric acid, potassium citrate, potassium metaphosphate, potassiumphosphate monobasic, sodium acetate, sodium citrate, sodium lactatesolution, dibasic sodium phosphate, monobasic sodium phosphate); Capsulelubricants (see tablet and capsule lubricant); Chelating agents (edetatedisodium, ethylenediaminetetraacetic acid and salts, edetic acid);Coating agents (sodium carboxymethylcellulose, cellulose acetate,cellulose acetate phthalate, ethylcellulose, gelatin, pharmaceuticalglaze, hydroxypropyl cellulose, hydroxypropyl methylcellulose,hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer,methylcellulose, polyethylene glycol, polyvinyl acetate phthalate,shellac, sucrose, titanium dioxide, carnauba wax, microcystalline wax,zein); Colorants (caramel, red, yellow, black or blends, ferric oxide);Complexing agents (ethylenediaminetetraacetic acid and salts (EDTA),edetic acid, gentisic acid ethanolmaide, oxyquinoline sulfate);Desiccants (calcium chloride, calcium sulfate, silicon dioxide);Emulsifying and/or solubilizing agents (acacia, cholesterol,diethanolamine (adjunct), glyceryl monostearate, lanolin alcohols,lecithin, mono- and di-glycerides, monoethanolamine (adjunct), oleicacid (adjunct), oleyl alcohol (stabilizer), poloxamer, polyoxyethylene50 stearate, polyoxyl 35 caster oil, polyoxyl 40 hydrogenated castoroil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate80, propylene glycol diacetate, propylene glycol monostearate, sodiumlauryl sulfate, sodium stearate, sorbitan monolaurate, soritanmonooleate, sorbitan monopalmitate, sorbitan monostearate, stearic acid,trolamine, emulsifying wax); Filtering aids (powdered cellulose,purified siliceous earth); Flavors and perfumes (anethole, benzaldehyde,ethyl vanillin, menthol, methyl salicylate, monosodium glutamate, orangeflower oil, peppermint, peppermint oil, peppermint spirit, rose oil,stronger rose water, thymol, tolu balsam tincture, vanilla, vanillatincture, vanillin); Glidants and/or anticaking agents (calciumsilicate, magnesium silicate, colloidal silicon dioxide, talc);Humectants (glycerin, hexylene glycol, propylene glycol, sorbitol);Plasticizers (castor oil, diacetylated monoglycerides, diethylphthalate, glycerin, mono- and di-acetylated monoglycerides,polyethylene glycol, propylene glycol, triacetin, triethyl citrate);Polymers (e.g., cellulose acetate, alkyl celloloses,hydroxyalkylcelloloses, acrylic polymers and copolymers); Solvents(acetone, alcohol, diluted alcohol, amylene hydrate, benzyl benzoate,butyl alcohol, carbon tetrachloride, chloroform, corn oil, cottonseedoil, ethyl acetate, glycerin, hexylene glycol, isopropyl alcohol, methylalcohol, methylene chloride, methyl isobutyl ketone, mineral oil, peanutoil, polyethylene glycol, propylene carbonate, propylene glycol, sesameoil, water for injection, sterile water for injection, sterile water forirrigation, purified water); Sorbents (powdered cellulose, charcoal,purified siliceous earth); Carbon dioxide sorbents (barium hydroxidelime, soda lime); Stiffening agents (hydrogenated castor oil,cetostearyl alcohol, cetyl alcohol, cetyl esters wax, hard fat,paraffin, polyethylene excipient, stearyl alcohol, emulsifying wax,white wax, yellow wax); Suspending and/or viscosity-increasing agents(acacia, agar, alginic acid, aluminum monostearate, bentonite, purifiedbentonite, magma bentonite, carbomer 934p, carboxymethylcellulosecalcium, carboxymethylcellulose sodium, carboxymethycellulose sodium 12,carrageenan, microcrystalline and carboxymethylcellulose sodiumcellulose, dextrin, gelatin, guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesiumaluminum silicate, methylcellulose, pectin, polyethylene oxide,polyvinyl alcohol, povidone, propylene glycol alginate, silicon dioxide,colloidal silicon dioxide, sodium alginate, tragacanth, xanthan gum);Sweetening agents (aspartame, dextrates, dextrose, excipient dextrose,fructose, mannitol, saccharin, calcium saccharin, sodium saccharin,sorbitol, solution sorbitol, sucrose, compressible sugar, confectioner'ssugar, syrup); Tablet binders (acacia, alginic acid, sodiumcarboxymethylcellulose, microcrystalline cellulose, dextrin,ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropylmethylcellulose, methycellulose, polyethylene oxide, povidone,pregelatinized starch, syrup); Tablet and/or capsule diluents (calciumcarbonate, dibasic calcium phosphate, tribasic calcium phosphate,calcium sulfate, microcrystalline cellulose, powdered cellulose,dextrates, dextrin, dextrose excipient, fructose, kaolin, lactose,mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressiblesugar, confectioner's sugar); Tablet disintegrants (alginic acid,microcrystalline cellulose, croscarmellose sodium, corspovidone,polacrilin potassium, sodium starch glycolate, starch, pregelatinizedstarch); Tablet and/or capsule lubricants (calcium stearate, glycerylbehenate, magnesium stearate, light mineral oil, polyethylene glycol,sodium stearyl fumarate, stearic acid, purified stearic acid, talc,hydrogenated vegetable oil, zinc stearate); Tonicity agent (dextrose,glycerin, mannitol, potassium chloride, sodium chloride); Vehicle:flavored and/or sweetened (aromatic elixir, compound benzaldehydeelixir, iso-alcoholic elixir, peppermint water, sorbitol solution,syrup, tolu balsam syrup); Vehicle: oleaginous (almond oil, corn oil,cottonseed oil, ethyl oleate, isopropyl myristate, isopropyl palmitate,mineral oil, light mineral oil, myristyl alcohol, octyldodecanol, oliveoil, peanut oil, persic oil, sesame oil, soybean oil, squalane);Vehicle: solid carrier (sugar spheres); Vehicle: sterile (bacteriostaticwater for injection, bacteriostatic sodium chloride injection);Viscosity-increasing (see suspending agent); Water repelling agent(cyclomethicone, dimethicone, simethicone); and Wetting and/orsolubilizing agent (benzalkonium chloride, benzethonium chloride,cetylpyridinium chloride, docusate sodium, nonoxynol 9, nonoxynol 10,octoxynol 9, poloxamer, polyoxyl 35 castor oil, polyoxyl 40,hydrogenated castor oil, polyoxyl 50 stearate, polyoxyl 10 oleyl ether,polyoxyl 20, cetostearyl ether, polyoxyl 40 stearate, polysorbate 20,polysorbate 40, polysorbate 60, polysorbate 80, sodium lauryl sulfate,sorbitan monolaureate, sorbitan monooleate, sorbitan monopalmitate,sorbitan monostearate, tyloxapol) may be used as excipients. This listis not meant to be exclusive, but instead merely representative of theclasses of excipients and the particular excipients which may be used indosage forms of the present invention.

The compounds of Formulas I, I-A, I-B, I-C and I-D can form salts whichare also within the scope of this invention. Reference to a compound ofthe Formula herein is understood to include reference to salts thereof,unless otherwise indicated. The term “salt(s)”, as employed herein,denotes acidic salts formed with inorganic and/or organic acids, as wellas basic salts formed with inorganic and/or organic bases. In addition,when a compound of the Formula contains both a basic moiety, such as,but not limited to a pyridine or imidazole, and an acidic moiety, suchas, but not limited to a carboxylic acid, zwitterions (“inner salts”)may be formed and are included within the term “salt(s)” as used herein.Pharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salts are preferred, although other salts are also useful.Salts of the compounds of the Formula may be formed, for example, byreacting a compound of Formula with an amount of acid or base, such asan equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Compounds of the various Formulas, and salts, solvates, esters andprodrugs thereof, may exist in their tautomeric form (for example, as anamide or imino ether). All such tautomeric forms are contemplated hereinas part of the present invention.

The compounds of the various Formulas may contain asymmetric or chiralcenters, and, therefore, exist in different stereoisomeric forms. It isintended that all stereoisomeric forms of the compounds of the variousFormulas as well as mixtures thereof, including racemic mixtures, formpart of the present invention. In addition, the present inventionembraces all geometric and positional isomers. For example, if acompound of the various Formulas incorporates a double bond or a fusedring, both the cis- and trans-forms, as well as mixtures, are embracedwithin the scope of the invention. Each compound herein disclosedincludes all the enantiomers that conform to the general structure ofthe compound. The compounds may be in a racemic or enantiomerically pureform, or any other form in terms of stereochemistry. The assay resultsmay reflect the data collected for the racemic form, theenantiomerically pure form, or any other form in terms ofstereochemistry.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of the various Formulas may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of the various Formulas may existin different tautomeric forms, and all such forms are embraced withinthe scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of the various Formulas incorporates a double bond or afused ring, both the cis- and trans-forms, as well as mixtures, areembraced within the scope of the invention. Also, for example, allketo-enol and imine-enamine forms of the compounds are included in theinvention.) Individual stereoisomers of the compounds of the inventionmay, for example, be substantially free of other isomers, or may beadmixed, for example, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled compounds of the various Formulas (e.g.,those labeled with ³H and ¹⁴C) are useful in compound and/or substratetissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e.,¹⁴C) isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of the various Formulascan generally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

Polymorphic forms of the compounds of the various Formulas, and of thesalts, solvates, esters and prodrugs of the compounds of the variousFormulas, are intended to be included in the present invention.

Benefits of the present invention include oral administration of anoptimal amount of a FASN inhibitor.

Benefits of the present invention include intravenous administration ofan optimal amount of a FASN inhibitor.

Benefits of the present invention include intraperitoneal administrationof an optimal amount of a FASN inhibitor.

Benefits of the present invention include intramural administration ofan optimal amount of a FASN inhibitor.

Benefits of the present invention include intramuscular administrationof an optimal amount of a FASN inhibitor.

Benefits of the present invention include subcutaneous administration ofan optimal amount of a FASN inhibitor.

Benefits of the present invention include intra-tumor administration ofan optimal amount of a FASN inhibitor.

Benefits of the present invention include intrathecal administration ofan optimal amount of a FASN inhibitor.

Benefits of the present invention include subdural administration of anoptimal amount of a FASN inhibitor.

Benefits of the present invention include periorbital administration ofan optimal amount of a FASN inhibitor.

Based on these results, the present invention has important implicationsfor the design of novel treatment strategies for patients with cancer,including leukemias and solid tumors, inflammatory diseases, viralinfections, osteoporosis, atherosclerosis; irritable or inflammatorybowel syndrome; diabetes, obesity and other conditions disclosed hereinor that are known to those skilled in the art.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

An aspect of the present invention concerns compounds disclosed herein.

An aspect of the present invention concerns compounds which are or canbe inhibitors of FASN.

An aspect of the present invention concerns the use of an inhibitor ofFASN for the preparation of a medicament used in the treatment,prevention, inhibition or elimination of tumors.

An aspect of the present invention concerns the use of an inhibitor ofFASN for the preparation of a medicament used in the treatment,prevention, inhibition or elimination of cancer.

An aspect of the present invention concerns the use of an inhibitor ofFASN for the preparation of a medicament used in the treatment,prevention, inhibition or elimination of cancer, where the cancer isselected from leukemia, lymphoma, ovarian cancer, breast cancer, uterinecancer, colon cancer, cervical cancer, lung cancer, prostate cancer,skin cancer, CNS cancer, bladder cancer, pancreatic cancer and Hodgkin'sdisease.

An aspect of the present invention concerns the use of an inhibitor ofFASN for the preparation of a medicament used in the treatment,prevention, inhibition or elimination of diabetes.

An aspect of the present invention concerns the use of an inhibitor ofFASN for the preparation of a medicament used in the treatment,prevention, inhibition or elimination of viral infectious diseases.

An aspect of the present invention concerns the use of an inhibitor ofFASN for the preparation of a medicament used in the treatment,prevention, inhibition or elimination of overweight or obesity.

An aspect of the present invention concerns the use of an inhibitor ofFASN for the preparation of a medicament used in the treatment,prevention, inhibition or elimination of uterine leiomyomata.

The present invention also describes one or more methods of synthesizingthe compounds of the present invention.

The invention also describes one or more uses of the compounds of thepresent invention.

The invention also describes one or more uses of the compounds of thepresent invention with an adjunctive agent such as use with TNF, GCSF,or other chemotherapeutic agents

The invention also describes one or more uses of the pharmaceuticalcompositions of the present invention.

An aspect of the present invention concerns the use as an inhibitor ofFASN for the preparation of a medicament used in the treatment ofinflammatory diseases.

An aspect of the present invention concerns the use as an inhibitor ofFASN for the preparation of a medicament used in the treatment ofinflammatory diseases, such as Irritable Bowel Syndrome or InflammatoryBowel Disease.

An aspect of the present invention concerns the use as an inhibitor ofFASN for the preparation of a medicament used in the treatment ofdisease of the bone such as osteoporosis.

An aspect of the present invention concerns the use as an inhibitor ofFASN for the preparation of a medicament used in the treatment ofdisease of the cardiovascular system, such as atherosclerosis.

An aspect of the present invention concerns the use as an inhibitor ofFASN for the preparation of a medicament used in the treatment ofdisease or a condition caused by an elevated level of FASN.

Such disease or condition is one or more selected from the groupconsisting of cancer, ovarian cancer, breast cancer, uterine cancer,colon cancer, cervical cancer, lung cancer, prostate cancer, skincancer, bladder cancer, pancreatic cancer, leukemia, lymphoma, Hodgkin'sdisease, viral infections, Human Immunodeficiency Virus, hepatitisvirus, herpes virus, herpes simplex, inflammatory disorders, irritablebowel syndrome, inflammatory bowel disease, rheumatoid arthritis,asthma, chronic obstructive pulmonary disease, osteoarthritis,osteoporosis, dermatitis, atoptic dermatitis, psoriasis, systemic lupuserythematosis, multiple sclerosis, psoriatic arthritis, ankylosingspondylitis, graft-versus-host disease, cerebrovascular accident,atherosclerosis, diabetes, glomerulonephiritis, metabolic syndrome,non-small cell lung cancer, small cell lung cancer, multiple myeloma,lymphomas, squamous cell cancers, kidney cancer, urethral and bladdercancers, cancers of head and neck, cancers of the brain and centralnervous system (CNS).

The inventive compounds of can be useful in the therapy of proliferativediseases such as cancer, autoimmune diseases, viral diseases, fungaldiseases, neurological/neurodegenerative disorders, arthritis,inflammation, anti-proliferative (e.g., ocular retinopathy), neuronal,alopecia and cardiovascular disease. Many of these diseases anddisorders are listed in U.S. Pat. No. 6,413,974, incorporated byreference herein.

More specifically, the compounds can be useful in the treatment of avariety of cancers, including (but not limited to) the following:carcinoma, including that of the bladder, breast, colon, kidney, liver,lung, including small cell lung cancer, non-small cell lung cancer, headand neck, esophagus, gall bladder, ovary, pancreas, stomach, cervix,thyroid, prostate, and skin, including squamous cell carcinoma;hematopoietic tumors of lymphoid lineage, including leukemia, acutelymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma,T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy celllymphoma, mantle cell lymphoma, myeloma, and Burkett's lymphoma;hematopoietic tumors of myeloid lineage, including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia; tumors of mesenchymal origin, including fibrosarcoma andrhabdomyosarcoma; tumors of the central and peripheral nervous system,including astrocytoma, neuroblastoma, glioma and schwannomas; and othertumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma,xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer andKaposi's sarcoma.

The compounds of the invention may induce or inhibit apoptosis.

The compounds of the invention may also be useful in the chemopreventionof cancer. Chemoprevention is defined as inhibiting the development ofinvasive cancer by either blocking the initiating mutagenic event or byblocking the progression of pre-malignant cells that have alreadysuffered an insult or inhibiting tumor relapse.

A further aspect of the invention is a method of inhibiting FASN in ananimal, said method comprising administering to said animal apharmaceutically acceptable amount of a compound of the invention to ananimal in need thereof.

A further aspect of the invention is a pharmaceutical formulationcomprising a compound of the invention.

Another embodiment of the invention comprises a pharmaceuticalformulation of the invention, wherein the pharmaceutical formulation,upon administration to a human, results in a decrease in tumor burden.

Still another embodiment of the invention is a pharmaceuticalformulation, further comprising one or more of an antineoplastic agent,a chemotherapeutic agent, or an adjunctive chemotherapeutic agent.

The pharmaceutical formulations of the invention may further comprise atherapeutic effective amount of an adjunctive chemotherapeutic agent.

The adjunctive chemotherapeutic agent may be an agent which modifiesblood cell growth and maturation. Non-limiting examples of adjunctivechemotherapeutic agent are filgrastim, pegfilgrastim and erythropoietin.

The invention is also directed to a method of treating or preventing adisorder associated with excessive rate of growth of cells in a mammalcomprising administering to the mammal an effective amount of thepharmaceutical formulation of the invention. Non-limiting examples ofdisorder include cancer or metastasis from malignant tumors.

Another aspect of the invention is a method of inhibiting tumor cellgrowth and rate of division in a mammal with cancer, or other disorderassociated with abnormally dividing cells comprising administering tothe mammal an effective amount of the pharmaceutical formulation of thisinvention.

Another embodiment of the invention is a method of treating bone paindue to excessive growth of a tumor or metastasis to bone in a mammal inneed thereof comprising administering to the mammal an effective amountof the pharmaceutical formulation of this invention.

Still another embodiment of the invention is a method for administeringan FASN-inhibitor-containing compound to a mammal in need thereofcomprising administering to the mammal the pharmaceutical formulation ofthe invention. In one embodiment, the mammal is a human.

A further embodiment of the invention is a method of preparing apharmaceutical formulation comprising mixing at least onepharmaceutically acceptable compound of the present invention, and,optionally, one or more pharmaceutically acceptable excipients oradditives.

The invention is also directed to methods of synthesizing compounds ofthe present invention.

Compounds of the Invention

The present invention relates to particular molecules andpharmaceutically acceptable salts or isomers thereof. The inventionfurther relates to molecules which are useful in inhibiting the enzymefatty acid synthase (FASN) and pharmaceutically acceptable salts orisomers thereof.

The invention is directed to compounds as described herein andpharmaceutically acceptable salts or isomers thereof, and pharmaceuticalcompositions comprising one or more compounds as described herein andpharmaceutically acceptable salts or isomers thereof. One aspect of thisinvention is the provision of compounds, compositions, and kits for FASNinhibition comprising a compound of formula I:

wherein

-   R₁ is a C₁-C₃ hydroxyl-alkyl either unsubstituted or substituted    with —CH₃ or —CH_(z)F_(3-z), 5 membered cycloalkyl either    unsubstituted or substituted with substituents selected from the    group consisting of deuterium, —R_(p), —OR_(p), —NHR_(p), and    —NR_(p)R_(p1),    -   or 3 or 4 membered cycloalkyl or heterocycloalkyl wherein (i)        the heteroatom ring member of the 3 or 4 membered        heterocycloalkyl is independently selected from O, S, or N,        and (ii) each of said 3 or 4 membered cycloalkyl or        heterocycloalkyl is either unsubstituted or optionally        substituted with substituents selected from the group consisting        of deuterium, —R_(a), —OR_(a), —NHR_(a), and —NR_(a)R_(a1);-   L is a 5-10 membered monocyclic or bicyclic alkyl or heteroalkyl    wherein (i) the heteroatom ring members of the 5-10 membered    monocyclic or bicyclic heteroalkyl are independently selected from    O, S, or N, and (ii) each of the 5-10 membered monocyclic or    bicyclic alkyl or heteroalkyl is either unsubstituted or optionally    substituted with substituents selected from the group consisting of    deuterium and —R_(b);-   A and B are independently O or S;-   Ar₁ is a 4-10 membered monocyclic or bicyclic aryl, heteroaryl or    heterocycloalkyl, wherein (i) said 4-10 membered monocyclic or    bicyclic heteroaryl or heterocycloalkyl have 1, 2, 3, or 4    heteroatoms which are independently selected from N, S or O,    and (ii) each of said 4-10 membered monocyclic or bicyclic aryl,    heteroaryl, or heterocycloalkyl is either unsubstituted or    optionally independently substituted with 1 or more substituents    which can be the same or different and are independently selected    from the group consisting of deuterium, halo, alkyl, —CH_(z)F_(3-z),    cyano, hydroxyl, hydroxylalkyl, amino, aminoalkyl-, (amino)alkoxy-,    —CONH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl),    —C(O)N(aryl)₂, —OCH_(z)F_(3-z), -alkyl, -alkenyl, -alkynyl, -alkoxy    or (alkoxyalkyl)amino-, —N(R_(c))—C(O)-alkyl, —N(R_(c))—C(O)-aryl,    -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the    proviso that no two adjacent ring heteroatoms are both S or both O;-   R₂ is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered    monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl    has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently    selected from N, S or O, and (ii) wherein each of said aryl,    heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted    or optionally substituted with 1 or more substituents which can be    the same or different and are independently selected from the group    consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-,    hydroxylcycoalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-,    hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH₂,    —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl, alkoxy-, -alkenyl,    -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl,    -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl,    —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl),    —O(heteroaryl), ONH₂, —C(O)NH(alkyl), —C(O)N(aryl)₂,    —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO₂), —NH(SO₂)alkyl,    —NH(SO₂)aryl, —NH(SO₂)heteroaryl, —N(SO₂)cycolalkyl, —C(O)N(alkyl)₂,    (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O)₂-alkyl,    —S(O)₂-aryl, —S(O)₂-cycloalkyl, —C(O)N(alkyl)₂, —C(O)alkyl,    —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl,    NH—C(O)-heterocycloalkyl-R_(d), —NH—C(O)— R_(d)—(O)alkyl,    —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl,    NH₂(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl,    NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R_(d))—C(O)-alkyl,    —NH(R_(d))—C(O)-aryl, —NH(R_(d))—S(O₂)cycloalkyl, —S(O₂)NH₂,    —S(O₂)NH(alkyl), —S(O₂)N(R_(d))cycloalkyl, —S(O₂)N(alkyl)₂,    —C(O)N(H)(alkyl), —C(O)N(R_(d)) (cycloalkyl), methylenedioxy,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), and -alkoxy;-   R_(p) and R_(p1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(a) and R_(a1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(b) is H, halo, C₁-C₄ alkyl, C₁-C₃ hydroxyl-alkyl, or C₃-C₄    cycloalkyl;-   R_(c) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   R_(d) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   and z is 0, 1 or 2;-   and pharmaceutically acceptable salts, solvates, esters, prodrugs    and isomers thereof.

In another embodiment, the compound of Formula I is represented by thecompound of Formula I-A:

wherein:

-   R₁ is a C₁-C₃ hydroxyl-alkyl either unsubstituted or substituted    with —CH₃ or —CH_(z)F_(3-z), 5 membered cycloalkyl either    unsubstituted or substituted with substituents selected from the    group consisting of deuterium, —R_(p), —OR_(p), —NHR_(p), and    —NR_(p)R_(p1),    -   or 3 or 4 membered cycloalkyl or heterocycloalkyl wherein (i)        the heteroatom ring member of the 3 or 4 membered        heterocycloalkyl is independently selected from O, S, or N,        and (ii) each of said 3 or 4 membered cycloalkyl or        heterocycloalkyl is either unsubstituted or optionally        substituted with substituents selected from the group consisting        of deuterium, —R_(a), —OR_(a), —NHR_(a), and —NR_(a)R_(a1);-   Ar₁ is a 4-10 membered monocyclic or bicyclic aryl, heteroaryl or    heterocycloalkyl, wherein (i) said 4-10 membered monocyclic or    bicyclic heteroaryl or heterocycloalkyl have 1, 2, 3, or 4    heteroatoms which are independently selected from N, S or O,    and (ii) each of said 4-10 membered monocyclic or bicyclic aryl,    heteroaryl, or heterocycloalkyl is either unsubstituted or    optionally independently substituted with 1 or more substituents    which can be the same or different and are independently selected    from the group consisting of deuterium, halo, alkyl, —CH_(z)F_(3-z),    cyano, hydroxyl, hydroxylalkyl, amino, aminoalkyl-, (amino)alkoxy-,    —CONH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl),    —C(O)N(aryl)₂, —OCH_(z)F_(3-z), -alkyl, -alkenyl, -alkynyl, -alkoxy    or (alkoxyalkyl)amino-, —N(R_(c))—C(O)-alkyl, —N(R_(c))—C(O)-aryl,    -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the    proviso that no two adjacent ring heteroatoms are both S or both O;-   R₂ is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered    monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl    has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently    selected from N, S or O, and (ii) wherein each of said aryl,    heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted    or optionally substituted with 1 or more substituents which can be    the same or different and are independently selected from the group    consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-,    hydroxylcycoalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-,    hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH₂,    —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl, alkoxy-, -alkenyl,    -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl,    -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl,    —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl),    —O(heteroaryl), ONH₂, —C(O)NH(alkyl), —C(O)N(aryl)₂,    —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO₂), —NH(SO₂)alkyl,    —NH(SO₂)aryl, —NH(SO₂)heteroaryl, —N(SO₂)cycolalkyl, —C(O)N(alkyl)₂,    (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O)₂-alkyl,    —S(O)₂-aryl, —S(O)₂-cycloalkyl, —C(O)N(alkyl)₂, —C(O)alkyl,    —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl,    NH—C(O)-heterocycloalkyl-R_(d), —NH—C(O)— R_(d)—(O)alkyl,    —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl,    NH₂(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl,    NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R_(d))—C(O)-alkyl,    —NH(R_(d))—C(O)-aryl, —NH(R_(d))—S(O₂)cycloalkyl, —S(O₂)NH₂,    —S(O₂)NH(alkyl), —S(O₂)N(R_(d))cycloalkyl, —S(O₂)N(alkyl)₂,    —C(O)N(H)(alkyl), —C(O)N(R_(d)) (cycloalkyl), methylenedioxy,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), and -alkoxy;-   R_(p) and R_(p1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(a) and R_(a1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(c) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   R_(d) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   and z is 0, 1 or 2;-   and pharmaceutically acceptable salts, solvates, esters, prodrugs    and isomers thereof.

In another embodiment, the compound of Formula I is represented by thecompound of Formula I-B:

Wherein:

-   Ar₁ is a 4-10 membered monocyclic or bicyclic aryl, heteroaryl or    heterocycloalkyl, wherein (i) said 4-10 membered monocyclic or    bicyclic heteroaryl or heterocycloalkyl have 1, 2, 3, or 4    heteroatoms which are independently selected from N, S or O,    and (ii) each of said 4-10 membered monocyclic or bicyclic aryl,    heteroaryl, or heterocycloalkyl is either unsubstituted or    optionally independently substituted with 1 or more substituents    which can be the same or different and are independently selected    from the group consisting of deuterium, halo, alkyl, —CH_(z)F_(3-z),    cyano, hydroxyl, hydroxylalkyl, amino, aminoalkyl-, (amino)alkoxy-,    —CONH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl),    —C(O)N(aryl)₂, —OCH_(z)F_(3-z), -alkyl, -alkenyl, -alkynyl, -alkoxy    or (alkoxyalkyl)amino-, —N(R_(c))—C(O)-alkyl, —N(R_(c))—C(O)-aryl,    -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the    proviso that no two adjacent ring heteroatoms are both S or both O;-   R₂ is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered    monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl    has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently    selected from N, S or O, and (ii) wherein each of said aryl,    heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted    or optionally substituted with 1 or more substituents which can be    the same or different and are independently selected from the group    consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-,    hydroxylcycoalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-,    hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH₂,    —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl, alkoxy-, -alkenyl,    -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl,    -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl,    —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl),    —O(heteroaryl), ONH₂, —C(O)NH(alkyl), —C(O)N(aryl)₂,    —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO₂), —NH(SO₂)alkyl,    —NH(SO₂)aryl, —NH(SO₂)heteroaryl, —N(SO₂)cycolalkyl, —C(O)N(alkyl)₂,    (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O)₂-alkyl,    —S(O)₂-aryl, —S(O)₂-cycloalkyl, —C(O)N(alkyl)₂, —C(O)alkyl,    —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl,    NH—C(O)-heterocycloalkyl-R_(d), —NH—C(O)— R_(d)—(O)alkyl,    —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl,    NH₂(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl,    NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R_(d))—C(O)-alkyl,    —NH(R_(d))—C(O)-aryl, —NH(R_(d))—S(O₂)cycloalkyl, —S(O₂)NH₂,    —S(O₂)NH(alkyl), —S(O₂)N(R_(d))cycloalkyl, —S(O₂)N(alkyl)₂,    —C(O)N(H)(alkyl), —C(O)N(R_(d)) (cycloalkyl), methylenedioxy,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), and -alkoxy;-   R_(c) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   R_(d) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   and z is 0, 1 or 2;-   and pharmaceutically acceptable salts, solvates, esters, prodrugs    and isomers thereof.

In another embodiment, the compound of Formula I is represented by thecompound of Formula I-C:

wherein:

-   R₁ is a C₁-C₃ hydroxyl-alkyl either unsubstituted or substituted    with —CH₃ or —CH_(z)F_(3-z), 5 membered cycloalkyl either    unsubstituted or substituted with substituents selected from the    group consisting of deuterium, —R_(p), —OR_(p), —NHR_(p), and    —NR_(p)R_(p1),    -   or 3 or 4 membered cycloalkyl or heterocycloalkyl wherein (i)        the heteroatom ring member of the 3 or 4 membered        heterocycloalkyl is independently selected from O, S, or N,        and (ii) each of said 3 or 4 membered cycloalkyl or        heterocycloalkyl is either unsubstituted or optionally        substituted with substituents selected from the group consisting        of deuterium, —R_(a), —OR_(a), —NHR_(a), and —NR_(a)R_(a1);-   R₂ is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered    monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl    has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently    selected from N, S or O, and (ii) wherein each of said aryl,    heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted    or optionally substituted with 1 or more substituents which can be    the same or different and are independently selected from the group    consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-,    hydroxylcycoalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-,    hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH₂,    —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl, alkoxy-, -alkenyl,    -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl,    -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl,    —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl),    —O(heteroaryl), ONH₂, —C(O)NH(alkyl), —C(O)N(aryl)₂,    —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO₂), —NH(SO₂)alkyl,    —NH(SO₂)aryl, —NH(SO₂)heteroaryl, —N(SO₂)cycolalkyl, —C(O)N(alkyl)₂,    (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O)₂-alkyl,    —S(O)₂-aryl, —S(O)₂-cycloalkyl, —C(O)N(alkyl)₂, —C(O)alkyl,    —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl,    NH—C(O)-heterocycloalkyl-R_(d), —NH—C(O)— R_(d)—(O)alkyl,    —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl,    NH₂(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl,    NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R_(d))—C(O)-alkyl,    —NH(R_(d))—C(O)-aryl, —NH(R_(d))—S(O₂)cycloalkyl, —S(O₂)NH₂,    —S(O₂)NH(alkyl), —S(O₂)N(R_(d))cycloalkyl, —S(O₂)N(alkyl)₂,    —C(O)N(H)(alkyl), —C(O)N(R_(d)) (cycloalkyl), methylenedioxy,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), and -alkoxy;-   R_(p) and R_(p1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(a) and R_(a1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(d) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   R_(q) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   and z is 0, 1 or 2;-   and pharmaceutically acceptable salts, solvates, esters, prodrugs    and isomers thereof.

In another embodiment, the compound of Formula I is represented by thecompound of Formula I-D:

wherein:

-   R₁′ is OH or NH₂;-   R₂ is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered    monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl    has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently    selected from N, S or O, and (ii) wherein each of said aryl,    heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted    or optionally substituted with 1 or more substituents which can be    the same or different and are independently selected from the group    consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-,    hydroxylcycoalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-,    hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH₂,    —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl, alkoxy-, -alkenyl,    -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl,    -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl,    —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl),    —O(heteroaryl), ONH₂, —C(O)NH(alkyl), —C(O)N(aryl)₂,    —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO₂), —NH(SO₂)alkyl,    —NH(SO₂)aryl, —NH(SO₂)heteroaryl, —N(SO₂)cycolalkyl, —C(O)N(alkyl)₂,    (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O)₂-alkyl,    —S(O)₂-aryl, —S(O)₂-cycloalkyl, —C(O)N(alkyl)₂, —C(O)alkyl,    —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl,    NH—C(O)-heterocycloalkyl-R_(d), —NH—C(O)— R_(d)—(O)alkyl,    —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl,    NH₂(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl,    NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R_(d))—C(O)-alkyl,    —NH(R_(d))—C(O)-aryl, —NH(R_(d))—S(O₂)cycloalkyl, —S(O₂)NH₂,    —S(O₂)NH(alkyl), —S(O₂)N(R_(d))cycloalkyl, —S(O₂)N(alkyl)₂,    —C(O)N(H)(alkyl), —C(O)N(R_(d)) (cycloalkyl), methylenedioxy,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), and -alkoxy;-   R_(d) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   and z is 0, 1 or 2;-   and pharmaceutically acceptable salts, solvates, esters, prodrugs    and isomers thereof.

In the compounds of Formulas I, I-A, I-B, I-C and I-D, the variousmoieties are independently selected.

The following embodiments are directed to Formulas I, I-A, I-B, I-C andI-D, as applicable. For any moieties that are not specifically defined,the previous definitions control. Further, the moieties aryl,heteroaryl, and heterocycloalkyl in these embodiments can beindependently unsubstituted or optionally substituted or optionallyfused as described earlier.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₁ is C₁-C₃ hydroxyl-alkyleither unsubstituted or substituted with —CH₃ or —CH_(z)F_(3-z), and A,B, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q)and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₁ is a 5 memberedcycloalkyl either unsubstituted or substituted with hydroxyl, and A, B,L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q) andz are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₁ is a 3 or 4 memberedcycloalkyl, and A, B, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b),R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₁ is a 3 or 4 memberedheterocycloalkyl, and A, B, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1),R_(b), R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₁ is

and A, B, L, Ar, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), , R_(q)and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₁ is

and A, B, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d),R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₁ is

and A, B, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d),R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₁ is

and A, B, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d),R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, A and B are O, and R₁, L,Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q) and zare as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, A and B are S, and R₁, L,Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q) and zare as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, either A or B is O, theother is S, and R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b),R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, L is a 5-10 memberedmonocyclic alkyl, and A, B, R₁, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1),R_(b), R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, L is a 5-10 memberedbicyclic alkyl, and A, B, R₁, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1),R_(b), R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, L is a 5-10 memberedmonocyclic heteroalkyl, and A, B, R₁, Ar₁, R₂, R_(p), R_(p1), R_(a),R_(a1), R_(b), R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, L is a 5-10 memberedbicyclic hetroalkyl, and A, B, R₁, Ar₁, R₂, R_(p), R_(p1), R_(a),R_(a1), R_(b), R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, L is

m is 1, 2, or 3, n is 0, 1, 2, or 3, and A, B, R₁, Ar₁, R₂, R_(p),R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, L is

and A, B, R₁, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c),R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, L is

and A, B, R₁, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c),R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, Ar₁ is an aryl, and A, B,R₁, L, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q) andz are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, Ar₁ is a heteroaryl, and A,B, R₁, L, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q)and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, Ar₁ is a 5-10 memberedmonocyclic aryl, and A, B, R₁, L, R₂, R_(p), R_(p1), R_(a), R_(a1),R_(b), R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, Ar₁ is a 5-10 memberedbicyclic aryl, and A, B, R₁, L, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b),R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, Ar₁ is a 5-10 memberedmonocyclic hetroaryl, and A, B, R₁, L, R₂, R_(p), R_(p1), R_(a), R_(a1),R_(b), R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, Ar₁ is a 5-10 memberedbicyclic heteroaryl, and A, B, R₁, L, R₂, R_(p), R_(p1), R_(a), R_(a1),R_(b), R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, Ar₁ is a substituted orunsubstituted 5 membered monocyclic aryl or heteroaryl and saidheteroaryl has 1 or 2 heteroatoms which are independently S or N, and A,B, R₁, L, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q)and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, Ar₁ is a substituted orunsubstituted form of

and A, B, R₁, L, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d),R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, Ar₁ is a substituted orunsubstituted 6 membered monocyclic aryl or heteroaryl and saidheteroaryl has 1 or 2 heteroatoms which are N, and A, B, R₁, L, R₂,R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q) and z are asdefined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, Ar₁ is a substituted orunsubstituted form of

Ph₁ is phenyl, pyridinyl, pyrazinyl, or pyrimidinyl, R_(c) is H, halo,or C₁-C₃ alkyl, and A, B, R₁, L, R₂, R_(p), R_(p1), R_(a), R_(a1),R_(b), R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, Ar₁ is a substituted orunsubstituted form of

and A, B, R₁, L, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d),R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, Ar₁ is a substituted orunsubstituted 6 membered monocyclic aryl, and A, B, R₁, L, R₂, R_(p),R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, Ar₁ is

R_(e) is H, halo, or C₁-C₃ alkyl, and A, B, R₁, L, R₂, R_(p), R_(p1),R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, Ar₁ is

and A, B, R₁, L, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d),R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, Ar₁ is a substituted orunsubstituted 9 membered 6,5-bicyclic heteroaryl and said heteroaryl has1, 2, or 3 heteroatoms which are independently O, S or N, and A, B, R₁,L, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q) and zare as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, Ar₁ is a substituted orunsubstituted form of

and said heteroaryl has 1, 2, or 3 heteroatoms which are independently Sor N, and A, B, R₁, L, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c),R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₂ is a substituted orunsubstituted aryl, and A, B, R₁, L, Ar₁, R_(p), R_(p1), R_(a), R_(a1),R_(b), R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₂ is a substituted orunsubstituted heteroaryl, and A, B, R₁, L, Ar₁, R_(p), R_(p1), R_(a),R_(a1), R_(b), R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₂ is a substituted orunsubstituted cycloalkyl, and A, B, R₁, L, Ar₁, R_(p), R_(p1), R_(a),R_(a1), R_(b), R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₂ is a substituted orunsubstituted heterocycloalkyl, and A, B, R₁, L, Ar₁, R_(p), R_(p1),R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₂ is a substituted orunsubstituted monocyclic or bicyclic 5-10 membered aryl or heteroaryl,and A, B, R₁, L, Ar₁, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d),R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₂ is a unsubstituted orsubstituted monocylic 6 membered aryl, and A, B, R₁, L, Ar₁, R_(p),R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₂ is

and A, B, R₁, L, Ar₁, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d),R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₂ is a substituted orunsubstituted bicyclic 8-10 membered aryl or 8-10 membered heteroaryl,and A, B, R₁, L, Ar₁, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d),R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₂ is a substituted orunsubstituted 8 membered 5,5 bicyclic heteroaryl and said heteroaryl has1, 2, 3, or 4 heteroatoms and said hetroatoms are independently O, S, orN, and A, B, R₁, L, Ar₁, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c),R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₂ is a substituted orunsubstituted form of

and A, B, R₁, L, Ar₁, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R₁,R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₂ is a substituted orunsubstituted 9 membered 6,5 bicyclic heteroaryl and said heteroaryl has1, 2, 3, or 4 heteroatoms and said hetroatoms are independently O, S, orN, and A, B, R₁, L, Ar₁, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c),R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₂ is a substituted orunsubstituted form of

and A, B, R₁, L, Ar₁, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(e), R_(d)and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₂ is a substituted orunsubstituted 10 membered 6,6 bicyclic aryl or heteroaryl and saidheteroaryl has 1, 2, 3, or 4 heteroatoms and said hetroatoms are O, S,or N, and A, B, R₁, L, Ar₁, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c),R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R₂ is a substituted orunsubstituted form of

and A, B, R₁, L, Ar₁, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d),R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(p) is H, and A, B, R₁,L, Ar₁, R₂, R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q) and z areas defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(p) is halo, and A, B,R₁, L, Ar₁, R₂, R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q) and zare as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(p) is C₁-C₄ alkyl, andA, B, R₁, L, Ar₁, R₂, R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q)and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(p) is C₃-C₄ cycloalkyl,and A, B, R₁, L, Ar₁, R₂, R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d),R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(p1) is H, and A, B, R₁,L, Ar₁, R₂, R_(p), R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q) and z areas defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(p1) is halo, and A, B,R₁, L, Ar₁, R₂, R_(p), R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q) and zare as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(p1) is C₁-C₄ alkyl, andA, B, R₁, L, Ar₁, R₂, R_(p), R_(a), R_(a1), R_(b), R_(c), R_(d), R_(q)and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(p1) is C₃-C₄ cycloalkyl,and A, B, R₁, L, Ar₁, R₂, R_(p), R_(a), R_(a1), R_(b), R_(c), R_(d),R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(a) is H, and A, B, R₁,L, Ar₁, R₂, R_(p), R_(p1), R_(a1), R_(b), R_(c), R_(d), R_(q) and z areas defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(a) is halo, and A, B,R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a1), R_(b), R_(c), R_(d), R_(q) and zare as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(a) is C₁-C₄ alkyl, andA, B, R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a1), R_(b), R_(c), R_(d), R_(q)and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(a) is C₃-C₄ cycloalkyl,and A, B, R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a1), R_(b), R_(c), R_(d),R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(a1) is H, and A, B, R₁,L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(b), R_(c), R_(d), R_(q) and z areas defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(a1) is halo, and A, B,R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(b), R_(c), R_(d), R_(q) and zare as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(a1) is C₁-C₄ alkyl, andA, B, R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(b), R_(c), R_(d), R_(q)and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(a1) is C₃-C₄ cycloalkyl,and A, B, R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(b), R_(c), R_(d),R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(b) is H, and A, B, R₁,L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(c), R_(d), R_(q) and z areas defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(b) is halo, and A, B,R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(d), R_(q) and z are asdefined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(b) is C₁-C₄ alkyl, andA, B, R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(c), R_(d), R_(q)and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(b) is C₁-C₃hydroxyl-alkyl, and A, B, R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1),R_(c), R_(d), R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(b) is C₃-C₄ cycloalkyl,and A, B, R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(c), R_(d),R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(c) is H, and A, B, R₁,L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(d), R_(q) and z areas defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(c) is halo, and A, B,R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(d), R_(q) and zare as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(c) is C₁-C₄ alkyl, andA, B, R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(d), R_(q)and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(c) is C₃-C₄ cycloalkyl,and A, B, R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(d),R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(d) is H, and A, B, R₁,L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(q) and z areas defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(d) is halo, and A, B,R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(q) and zare as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(d) is C₁-C₄ alkyl, andA, B, R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(q)and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(d) is C₃-C₄ cycloalkyl,and A, B, R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c),R_(q) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(q) is H, and A, B, R₁,L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d) and z areas defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(q) is halo, and A, B,R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d) and zare as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(q) is C₁-C₄ alkyl, andA, B, R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d)and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R_(q) is C₃-C₄ cycloalkyl,and A, B, R₁, L, Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c),R_(d) and z are as defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, z is 0, and A, B, R₁, L,Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d) and R_(q) areas defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, z is 1 and A, B, R₁, L,Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d) and R_(q) areas defined.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, z is 2 and A, B, R₁, L,Ar₁, R₂, R_(p), R_(p1), R_(a), R_(a1), R_(b), R_(c), R_(d) and R_(q) areas defined.

An embodiment of the invention is the provision of a compound asdescribed in Formulas I, I-A, I-B, I-C or I-D, wherein R₂ is not asubstituted or unsubstituted form of

where X is N or CH.

An embodiment of the invention is the provision of a compound asdescribed in Formulas I, I-A, I-B, I-C, or I-D wherein when Ar₁ is

connected to

at position 1, and X₁ and X₂ are independently N or C—R_(z), and R_(y)and R_(z) are any substituent, then R_(x) does not include alkynyl,alkenyl, aryl, 5-14 membered heterocyclic, 5-14 membered heteroaromatic,or 4-9 membered carbocyclic.

An embodiment of the invention is the provision of a compound asdescribed in Formulas I, I-A, I-B, I-C, or I-D wherein when R₂ is

Ar₁ is not a substituted or unsubstituted form of

An embodiment of the invention is the provision of a compound asdescribed in Formulas I, I-A, I-B, I-C, or I-D wherein when Ar is asubstituted or unsubstituted form of a 5 membered heteroaryl, Ar₁ is

In another embodiment, the invention is further illustrated by thecompounds shown in Table 1, which lists the IUPAC names and thestructures of the compounds.

TABLE 1 IUPAC Name Compound Structure 1-({4-[(4-phenylphenyl)carbonyl]piperazin- 1-yl}carbonyl)cyclopropan-1-ol

2-hydroxy-2-methyl-1-{4-[(4- phenylphenyl)carbonyl]piperazin-1-yl}propan-1-one

2-hydroxy-1-{4-[(4- phenylphenyl)carbonyl]piperazin- 1-yl}ethan-1-one

1-({4-[(4- phenylphenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopentan-1-ol

3,3,3-trifluoro-2-hydroxy-2- methyl-1-{4-[(4-phenylphenyl)carbonyl]piperazin- 1-yl}propan-1-one

1-[(4-{[4-(3-methyl- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(4-methyl- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-fluoro-3-methoxy- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-fluoro-4-methyl- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-fluoro-4-methoxy- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-chloro-4-fluoro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(3-chloro-4-fluoro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(4-chloro-2-fluoro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2,4-dichloro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5-fluoro-2-methyl- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(3-fluoro-4-methyl- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2,3-dichloro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2,5-dichloro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(4-chloro-3-fluoro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2,5-difluoro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(3,4-dichloro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2,3-difluoro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-methyl-1H-indol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[2-methyoxy-4- (1H-pyrazol-1-yl)phenyl]phenyl}carbonyl)piperazin- 1-yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(2-fluoro-5-methyl- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[2-chloro-5-(trifluorometh-yl)phenyl]phenyl}carbonyl)piperazin- 1-yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(4-chloro-2-methoxy- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(3-chloro-2-methoxy- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(4,5-difluoro-2-methoxy- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[2-fluoro-3-(trifluorometh-yl)phenyl]phenyl}carbonyl)piperazin- 1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[4-chloro-2-(trifluorometh-yl)phenyl]phenyl}carbonyl)piperazin- 1-yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(2-chloro-4-methoxy- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[5-chloro-2-(propan-2- yloxy)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[3-fluoro-5-(trifluorometh-yl)phenyl]phenyl}carbonyl)piperazin- 1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[2-methoxy-5-(trifluorometh-oxy)phenyl]phenyl}carbonyl)piperazin- 1-yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(3-fluoro-2-methoxy- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(3-methoxypyridin-4- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(quinolin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(isoquinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-({4-[(4-{imidazo[1,2-a]pyridin-6- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-[(4-{[4-(1,3-benzothiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[6-(trifluoromethyl)pyridin- 3-yl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(5-chloro-2-fluoro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(6-methylpyridin- 3-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2,6-dimethoxypyridin- 3-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5-fluoropyridin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-methyl-1H-indol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-chloro-5-fluoro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-fluoro-5-methoxy- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-fluoro-3-methyl- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[4-fluoro-2-(trifluorometh-yl)phenyl]phenyl}carbonyl)piperazin- 1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[2-chloro-5- (hydroxymethyl)phen-yl)phenyl]phenyl}carbonyl)piperazin- 1-yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(2-methyl-2H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-methyl-1H-indazol-7- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1H-indol-4- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

N-cyclopropyl-3-[4-({4-[(1-hydroxy- cyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]benzamide

N-{3-[4-({4-[(1-hydroxy- cyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}ethane- 1-sulfonamide

4-fluoro-3-[4-({4-[(1-hydroxy- cyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-N- methylbenzamide

4-fluoro-3-[4-({4-[(1-hydroxy- cyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-N- (propan-2-yl)benzamide

1-[(4-{[4-(2,4-dichloro-3-methoxy- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[2-fluoro-3-(propan-2- yloxy)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[2-fluoro-3-(trifluorometh-oxy)phenyl]phenyl}carbonyl)piperazin- 1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[3-(cyclopropylmeth- oxy)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

5-fluoro-2-[4-({4-[(1-hydroxy- cyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]benzonitrile

1-[(4-{[4-(1-methyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-methyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[6-(1-methyl-1H-indol-5- yl)pyridin-3-yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[5-(1-methyl-1H-indol-5- yl)pyridin-2-yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-fluoro-4-(1-methyl-1H-indol- 5-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-fluoro-4-(quinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

2-methoxy-2-methyl-1-{4-[(4- phenylphenyl)carbonyl]piperazin-1-yl}propan-1-one

(2S)-2-hydroxy-1-{4-[(4- phenylphenyl)carbonyl]piperazin-1-yl}propan-1-one

1-[(4-{[4-(quinolin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

1-[(4-{[2-chloro-4-(quinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-chloro-4-(1-methyl-1H-indol- 5-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[6-(quinolin-6-yl)pyridin-3- yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-methyl-2-(1-methyl-1H- indol-5-yl)-1,3-thiazol-5-yl]carbonyl}piperazin- 1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-methyl-2-(quinolin-3-yl)-1,3- thiazol-5-yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-(1,3-benzothiazol-5-yl)-4- methyl-1,3-thiazol-5-yl]carbonyl}piperazin- 1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[3-fluoro-4-(quinolin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[3-fluoro-4-(quinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-benzothiazol-5-yl)-3- fluorophenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[3-methyl-4-(1-methyl-1H-indol- 5-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[3-methyl-4-(quinolin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[3-methyl-4-(quinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-benzothiazol-5-yl)-3- methylphenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-chloro-4-(quinolin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-benzothiazol-5-yl)-2- chlorophenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[3-chloro-4-(1-methyl-1H-indol- 5-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[3-chloro-4-(quinolin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[3-chloro-4-(quinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-benzothiazol-5-yl)-3- chlorophenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-methyl-1H-indol-5- yl)-2-(trifluorometh-yl)phenyl]carbonyl}piperazin- 1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(quinolin-6-yl)-2- (trifluorometh-yl)phenyl]carbonyl}piperazin- 1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[3-methoxy-4-(quinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-methoxy-4-(quinolin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-methoxy-4-(quinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-benzothiazol-5-yl)-2- methoxyphenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[5-(quinolin-6-yl)pyrimidin-2- yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[5-(1-methyl-1H-indol-5- yl)pyrazin-2-yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[5-(quinolin-3-yl)pyrazin-2- yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[5-(quinolin-6-yl)pyrazin-2- yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-({4-[(4- phenylphenyl)carbonyl]piperazin-1-yl}carbonyl)cyclobutan-1-ol

1-[(4-{[4-(isoquinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

1-{[(2S,5R)-4-{[4-isoquinolin-6- yl)phenyl]carbonyl}-2,5-dimethylpiperazin- 1-yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(1H-indol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

3-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]quinoline

5-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl}phenyl]-1H-indole

1-[(4-{[2-fluoro-4-(quinolin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

6-[4-([4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]isoquinoline

l-[(4-{[4-(1,5-naphthyridin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-benzofuran-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-({4-[(4- phenoxyphenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-[(4-{[2-fluoro-4-(7-fluoro-1H-indol- 5-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({3-chloro-4-[1-(trifluoromethyl)- 1H-indol-5-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(1,3-benzoxazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-benzothiazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({3-chloro-4-[1-(propan-2-yl)- 1H-indol-5-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(1H-1,3-benzodiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

5-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-3- carbonitrile

3-[3-fluoro-4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]quinolin-2-ol

1-[(4-{[4-(1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-fluoro-4-(2-methoxyquinolin- 3-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(4-chloroquinolin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(7-fluoro-1H-indol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(quinolin-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-benzothiazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-methoxyquinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[1-(trifluoromethyl)-1H- indol-5-yl]phenyl}carbonyl)piperazin- 1-yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(6-methoxynaphthalen-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5-chloro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(6-chloro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5-fluoro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(6-fluoro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(6-methoxynaphthalen-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5-chloro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(6-chloro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5-fluoro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(6-fluoro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-({4-[(4-{pyrazolo[1,5-a]pyridin-2- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-{[4-({4-[1-(propan-2-yl)-1H-indazol- 5-yl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-[(4-{[6-(2-methoxyquinolin-6- yl)pyridin-3-yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[5-(2-methoxyquinolin-6- yl)pyridin-2-yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({6-phenylimidazo[1,2-a]pyridin- 2-yl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-[(4-{[6-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl]carbonyl}piperazin- 1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[5-(4-chloro-2-fluoro- phenyl)pyridin-2-yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[6-(4-chloro-2-fluoro- phenyl)pyridin-3-yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[5-(4-chloro-2-fluorophen- yl)pyrimidin-2-yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-fluoro-4-(6-fluoro- quinolin-2-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-fluoro-4-(6-methoxy- quinolin-2-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2,3-difluoro-4-(quinolin-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2,3-difluoro-4-(6-fluoro-quinolin-2-yl)phenyl]carbonyl}piperazin- 1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2,3-difluoro-4-(6-methoxy-quinolin-2-yl)phenyl]carbonyl}piperazin- 1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(6-fluoroquinolin-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(6-methoxyquinolin-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-({4-[(4-{imidazo[1,2-a]pyridin-2- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-[(4-{[4-(2,1,3-benzoxadiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phen- yl}benzenesulfonamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phen- yl}methanesulfonamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}propane- 2-sulfonamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- propanesulfonamide

1-[(4-{[4-(isoquinolin-1- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[7-(trifluoromethyl)quinolin-4-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(6-methoxy-4-methylquinolin- 2-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5-chloro-1H-1,3-benzodiazol-2-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(4-chloro-1H-1,3-benzodiazol-2-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5,6-difluoro-1H-1,3- benzodiazol-2-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5-methoxy-1H-1,3- benzodiazol-2-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5-fluoro-1H-1,3-benzodiazol-2-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-dimethyl-1H-indazol- 5-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

6-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-2,3- dihydro-1,3-benzoxazol-2-one

5-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-2,3- dihydro-1,3-benzoxazol-2-one

1-[(4-{[4-(3-methyl-1,2-benzoxazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1H-1,3-benzodiazol-4- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-benzoxazol-4- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(quinolin-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1H-indazol-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-({4-[(4-{furo[3,2-b]pyridin-5- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-({4-[(4-{furo[3,2-c]pyridin-4- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-({4-[(4-{[1,2,4]triazolo[4,3- b]pyridazin-6-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol

1-({4-[(4-{imidazo[1,2-a]pyrazin-6- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-({4-[(4-{1H-pyrrolo[3,2-b]pyridin- 5-yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-({4-[(4-{imidazo[1,2-b]pyridazin- 6-yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-[(4-{[4-(1-methyl-1H-1,3- benzodiazol-5-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2,1,3-benzothiadiazol-4- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[2-(trifluorometh- yl)imidazo[1,2-a]pyridin-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-({4-[(4-{6-chloroimidazo[1,2- a]pyridin-3-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol

1-[(4-{[4-(2-methyl-2H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-({4-[(4-{imidazo[1,2-a]pyrimidin- 7-yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

5-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-2- carbonitrile

2-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,3- benzoxazole-6-carbonitrile

1-[(4-{[4-(2,1,3-benzothiadiazol- 5-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2H-1,2,3-benzotriazol- 5-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-({4-[(2-phenyl-1,3-benzothiazol-6- yl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-[(4-{[2-(4-fluorophenyl)-1,3- benzothiazol-6-yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

2-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,3- benzoxazole-5-carbonitrile

3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,2- dihydroquinolin-2-one

1-({4-[(2-chloro-4-{imidazo[1,2- a]pyridin-2-yl}phenyl)carbonyl]piperazin- 1-yl}carbonyl)cyclopropan-1-ol

1-({4-[(3-phenoxyphenyl)carbon- yl]piperazin-1-yl}carbonyl)cyclo-propan-1-ol

1-({4-[(4-{6-fluoroimidazo[1,2- a]pyridin-2-yl}phenyl)carbonyl]piperazin- 1-yl}carbonyl)cyclopropan-1-ol

1-({4-[(4-{6-methoxyimidazo[1,2 a]pyridin-2-yl}phenyl)carbonyl]piperazin- 1-yl}carbonyl)cyclopropan-1-ol

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- propanecarboxamide

1-{[(2S)-4-{[4-(4-chloro-2-fluoro- phenyl)phenyl]carbonyl}-2-(hydroxymethyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(3-cyclopropoxy- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

N-cyclopropyl-3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]benzene-1- sulfonamide

5-[4-({4-[(1-hydroxycycloprop- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-2- carboxamide

1-[(4-{[4-(3-chlorophenyl)phen- yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(4-chlorophenyl)phen- yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[(3S)-4-{[4-(4-chloro-2-fluoro- phenyl)phenyl]carbonyl}-3-(hydroxymethyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(1H-indol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-({4-[(4-{3-chloroimidazo[1,2- a]pyridin-2-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol

1-[(4-{[4-(1-methyl-1H-1,3- benzodiazol-2-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

3-[3-chloro-4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-N-cyclopropyl- benzene-1-sulfonamide

1-({4-[(2-chloro-4-{furo[3,2-b]pyridin-5-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol

1-[(4-{[2-chloro-4-(1-methyl-1H-1,3- benzodiazol-5-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

N-{3-[3-chloro-4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- propanesulfonamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- butanecarboxamide

1-{[4-({4-[3-(cyclopropanesulfon- yl)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

N-{5-[3-chloro-4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]pyridin-3- yl}cyclopropanesulfonamide

N-{5-[3-chloro-4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]pyridin-3- yl}-cyclopropanecarboxamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}oxetane-3- carboxamide

1-{[4-({4-[3-(cyclopropanesulfon- yl)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclobutan-1-ol

1-({4-[3-(cyclopropane- sulfonyl)phenyl]phenyl}carbonyl)-4-[(oxetan-2-yl)carbonyl]piperazine

1-({4-[(4-{3-chloroimidazo[1,2- a]pyridin-2-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclobutan-1-ol

1-[(4-{3-chloroimidazo[1,2-a]pyridin-2-yl}phenyl)carbonyl]-4-[(oxetan-2- yl)carbonyl]piperazine

1-[(4-{[4-(3-cyclopropxy- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

1-{[4-(3-cyclopropoxy- phenyl)phenyl]carbonyl}-4-[(oxetan-2-yl)carbonyl]piperazine

N-{3-[4-({4-[(1-hydroxycyclo- butyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- propanecarboxamide

N-{3-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- propanecarboxamide

3-[4-({4-[(1-hydroxycyclo- butyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,2- dihydroquinolin-2-one

3-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-1,2-dihydroquinolin-2-one

5-[4-({4-[(1-hydroxycyclo- butyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-2- carbonitrile

5-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-2- carbonitrile

1-[(4-{[4-(1-methyl-1H-1,3- benzodiazol-5-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclobutan-1-ol

1-methyl-5-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-1,3- benzodiazole

1-({4-[(4-{imidazo[1,2-b]pyridazin-6- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclobutan-1-ol

1-[(4-{imidazo[1,2-b]pyridazin-6- yl}phenyl)carbonyl]-4-[(oxetan-2-yl)carbonyl]piperazine

1-({4-[(4-{furo[3,2-b]pyridin-5- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclobutan-1-ol

1-[(4-{furo[3,2-b]pyridin-5- yl}phenyl)carbonyl]-4-[(oxetan-2-yl)carbonyl]piperazine

1-[(4-{[4-(1H-indazol-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

3-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indazole

1-[(4-{[4-(1,3-dimethyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

1,3-dimethyl-5-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indazole

N-{3-[4-({4-[(1-hydroxycyclo- butyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- propanesulfonamide

N-{3-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- propanesulfonamide

1-[(4-{[4-(6-fluoro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

6-fluoro-2-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,3- benzoxazole

1-[(4-{[4-(6-chloro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

6-chloro-2-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,3- benzoxazole

5-[4-({4-[(1-hydroxycyclo- butyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-3- carbonitrile

5-[4-({4-[(oxetan-2 yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-3- carbonitrile

1-[(4-{[4-(1,3-benzothiazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

2-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-1,3-benzothiazole

1-[(4-{[4-(quinolin-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

2-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]quinoline

1-[(4-{[4-(1H-1,3-benzodiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

5-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-1,3- benzodiazole

1-[(4-{[4-(1,3-benzothiazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

6-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-1,3-benzothiazole

1-[(4-{[4-(1,3-benzoxazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

5-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-1,3-benzoxazole

1-[(4-{[4-(1,3-benzothiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

5-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-1,3-benzothiazole

1-[(4-{[4-(1-methyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

1-methyl-6-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indazole

N-cyclopropyl-3-[4-({4-[(1- hydroxycyclobut- yl)carbonyl]piperazin-1-yl}carbonyl)pheny]benzamide

N-cyclopropyl-3-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)pheny]benzamide

1-[(4-{[4-(2-methyl-2H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

2-methyl-6-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-2H-indazole

1-[(4-{[4-(4-chloro-2-fluoro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

1-{[4-(4-chloro-2-fluoro- phenyl)phenyl]carbonyl}-4-[(oxetan-2-yl)carbonyl]piperazine

1-[(4-{[4-(5-chloro-2-fluoro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

1-{[4-(5-chloro-2-fluoro- phenyl)phenyl]carbonyl}-4-[(oxetan-2-yl)carbonyl]piperazine

1-{[4-({4-[3-(cyclopropanesulfon- yl)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclobutan-1-amine

1-{[4-({4-[3-(cyclopropanesulfon- yl)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-amine

1-({4-[(4-{3-chloroimidazo[1,2- a]pyridin-2-yl}phenyl)carbonyl]piperazin- 1-yl}carbonyl)cyclobutan-1-amine

1-({4-[(4-{3-chloroimidazo[1,2- a]pyridin-2-yl}phenyl)carbonyl]piperazin- 1-yl}carbonyl)cyclopropan-1-amine

1-[(4-{[4-(3-cyclopropoxy- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(3-cyclopropoxy- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

N-{3-[4-({4-[(1-aminocyclo- butyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- propanecarboxamide

N-{3-[4-({4-[(1-aminocyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- propanecarboxamide

3-[4-({4-[(1-aminocyclo- butyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,2- dihydroquinolin-2-one

3-[4-({4-[(1-aminocyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,2- dihydroquinolin-2-one

5-[4-({4-[(1-aminocyclo- butyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-2- carbonitrile

5-[4-({4-[(1-aminocyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-2- carbonitrile

1-[(4-{[4-(1-methyl-1H-1,3- benzodiazol-5-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(1-methyl-1H-1,3- benzodiazol-5-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-amine

1-({4-[(4-{imidazo[1,2-b]pyridazin-6- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclobutan-1-amine

1-({4-[(4-{imidazo[1,2-b]pyridazin-6- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-amine

1-({4-[(4-{furo[3,2-b]pyridin-5- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclobutan-1-amine

1-({4-[(4-{furo[3,2-b]pyridin-5- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-amine

1-[(4-{[4-(1H-indazol-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(1H-indazol-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(1,3-dimethyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(1,3-dimethyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

N-{3-[4-({4-[(1-aminocyclo- butyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- propanesulfonamide

N-{3-[4-({4-[(1-aminocyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- propanesulfonamide

1-[(4-{[4-(6-fluoro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(6-fluoro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(6-chloro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(6-chloro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

5-[4-({4-[(1-aminocyclo- butyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-3- carbonitrile

5-[4-({4-[(1-aminocyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-3- carbonitrile

1-[(4-{[4-(1,3-benzothiazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(1,3-benzothiazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(quinolin-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(quinolin-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(1H-1,3-benzodiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(1H-1,3-benzodiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(1,3-benzothiazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(1,3-benzothiazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(1,3-benzoxazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(1,3-benzoxazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(1,3-benzothiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(1,3-benzothiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(1-methyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(1-methyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

3-[4-({4-[(1-aminocyclo- butyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-N- cyclopropylbenzamide

3-[4-({4-[(1-aminocyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-N- cyclopropylbenzamide

1-[(4-{[4-(2-methyl-2H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(2-methyl-2H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(4-chloro-2-fluoro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(4-chloro-2-fluoro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(5-chloro-2-fluoro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(5-chloro-2-fluoro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

3-{[4-({4-[3-(cyclopropanesulfon- yl)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}oxetan-3-ol

3-{[4-({4-[3-(cyclopropanesulfon- yl)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}oxetan-3-amine

3-({4-[(4-{3-chloroimidazo[1,2- a]pyridin-2-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)oxetan-3-ol

3-({4-[(4-{3-chloroimidazo[1,2- a]pyridin-2-yl}phenyl)carbonyl]piperazin- 1-yl}carbonyl)oxetan-3-amine

3-[(4-{[4-(3-cyclopropoxyphen- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(3-cyclopropoxyphen- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

N-{3-[4-({4-[(3-hydroxyoxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclopro- panecarboxamide

N-{3-[4-({4-[(3-aminooxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclopro- panecarboxamide

3-[4-({4-[(3-hydroxyoxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,2- dihydroquinolin-2-one

3-[4-({4-[(3-aminooxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,2- dihydroquinolin-2-one

5-[4-({4-[(3-hydroxyoxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-2- carbonitrile

5-[4-({4-[(3-aminooxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-2- carbonitrile

3-[(4-{[4-(1-methyl-1H-1,3- benzodiazol-5-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(1-methyl-1H-1,3- benzodiazol-5-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]oxetan-3-amine

3-({4-[(4-{imidazo[1,2- b]pyridazin-6- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)oxetan-3-ol

3-({4-[(4-{imidazo[1,2- b]pyridazin-6- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)oxetan-3-amine

3-({4-[(4-{furo[3,2-b]pyridin-5- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)oxetan-3-ol

3-({4-[(4-{furo[3,2-b]pyridin-5- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)oxetan-3-amine

3-[(4-{[4-(1H-indazol-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(1H-indazol-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(1,3-dimethyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(1,3-dimethyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

N-{3-[4-({4-[(3-hydroxyoxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- propanesulfonamide

N-{3-[4-({4-[(3-aminooxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- propanesulfonamide

3-[(4-{[4-(6-fluoro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(6-fluoro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(6-chloro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(6-chloro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

5-[4-({4-[(3-hydroxyoxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-3- carbonitrile

5-[4-({4-[(3-aminooxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-3- carbonitrile

3-[(4-{[4-(1,3-benzothiazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(1,3-benzothiazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(quinolin-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(quinolin-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(1H-1,3-benzodiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(1H-1,3-benzodiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(1,3-benzothiazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(1,3-benzothiazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(1,3-benzoxazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(1,3-benzoxazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(1,3-benzothiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(1,3-benzothiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(1-methyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(1-methyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

N-cyclopropyl-3-[4-({4-[(3- hydroxyoxetan-3-yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]benzamide

3-[4-({4-[(3-aminooxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-N- cyclopropylbenzamide

3-[(4-{[4-(2-methyl-2H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(2-methyl-2H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(4-chloro-2-fluoro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(4-chloro-2-fluoro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(5-chloro-2-fluoro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(5-chloro-2-fluoro- phenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

1-({4-[(4-{5-chloro-[1,3]thiazolo[5,4- d][1,3]thiazol-2-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol

1-{[4-({4-[4-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-({4-[(4-{imidazo[2,1- b][1,3,4]thiadiazol-2yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol

1-({4-[(4-{6H-thieno[2,3-b]pyrrol-2- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-({4-[(4-{4H-thieno[3,2-b]pyrrol-3- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

2-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-3H-pyrrolizin- 3-one

6-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-3H- pyrrolizin-3-one

1-[(4-{[4-(1-methanesulfonyl-1H-indol- 6-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[4-(1-methyl-1H-pyrazol-3-yl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(1-ethyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-cyclobutyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[1-(oxetan-3-yl)-1H-indazol- 5-yl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(propan-2-yl)-1H-indazol- 5-yl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(2-methoxyethyl)-1H-indazol-5-yl]phenyl}carbonyl)piperazin- 1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(cyclopropylmethyl)-1H-indazol-5-yl]phenyl}carbonyl)piperazin- 1-yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(1-propyl-1H-indazol-5- yl)phenyl]carbonyl)piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[1-(cyclobutylmethyl)-1H- indazol-5-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(oxetan-3-ylmethyl)-1H- indazol-5-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(2-hydroxymethyl)-1H- indazol-5-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[4-(1H-pyrazol-5- yl)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[4-(1H-pyrazol-4- yl)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[4-(2-methyl-2H-1,2,3- triazol-4-yl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[4-(1-methyl-1H-1,2,3- triazol-4-yl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(1-methanesulfonyl-1H- indol-5-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[1-(cyclopropanesulfonyl)- 1H-indol-5-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(cyclopropanesulfonyl)- 1H-indol-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[2-(hydroxymethyl)-1H- indol-5-yl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

2-{5-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl]carbonyl)phenyl]-1H-indol-3- yl}acetonitrile

1-{[4-({4-[3-(2-hydroxyethyl)-1H- indol-5-yl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

5-[4-({4-[(1-hydroxycyclo- proyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1-benzofuran- 2-carbonitrile

1-[(4-({4-(3-amino-1-methyl-1H- indazol-6-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-aminoisoquinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(3-aminoisoquinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-dimethylisoquinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[3-(methoxymethyl)-1 methyl-1H-indazol-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[3-(hydroxymethyl)-1- methyl-1H-indazol-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(2-methylquinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-aminoquinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-ethyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-cyclobutyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[1-(oxetan-3-yl)-1H-indazol- 6-yl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(propan-2-yl)-1H-indazol- 6-yl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(2-methoxyethyl)-1H- indazol-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(cyclopropylmethyl)- 1H-indazol-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(1-propyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[1-(cyclobutylmethyl)-1H- indazol-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(oxetan-3-ylmethyl)-1H- indazol-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(2-hydroxyethyl)-1H- indazol-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(1-cyclopropyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

N-{3-[4-({4-[(1-hydroxycycloprop- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-N- methylcyclopropanecarboxamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-N- methylcyclobutanecarboxamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-N- methylcyclobutanesulfonamide

N-cyclopropyl-3-[4-({4-[(1- hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-N- methylbenzene-1-sulfonamide

N-cyclopropyl-3-[4-({4-[(1- hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-N- methylbenzamide

2-cyclobutyl-N-{3-[4-({4-[(1- hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}acetamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-1- methylazetidine-3-carboxamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-3- methyloxetane-3-carboxamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-2- (oxetan-3-yl)acetamide

3-fluoro-N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- butane-1-carboxamide

3-ethyl-N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}oxetane- 3-carboxamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}pro- panamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-2- methylpropanamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}butanamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-2- methoxyacetamide

2-cyclopropyl-N-{3-[4-({4-[(1- hydroxycyclo-propyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]phenyl}acetamide

2,2-difluoro-N-{3-[4-({4-[(1- hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}acetamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-1- methylcyclopropane-1-carboxamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- pentanecarboxamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- hexanecarboxamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}oxane- 4-carboxamide

1-cyclopropyl-N-{3-[4-({4-[(1- hydroxycyclo-propyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]phenyl}meth-anesulfonamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-2- methylpropane-1-sulfonamide

1,1-difluoro-N-{3-[4-({4-[(1- hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}methane- sulfonamide

3,3,3-trifluoro-N-{3-[4-({4-[(1- hydroxycyclo-propyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]phenyl}propane-1-sulfonamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-1- methylcyclopropane-1-sulfonamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- butanesulfonamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}oxolane- 3-sulfonamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- pentanesulfonamide

2,2-difluoro-N-{3-[4-({4-[(1- hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}ethane- 1-sulfonamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-2- methoxyethane-1-sulfonamide

1-cyclobutyl-N-{3-[4-({4-[(1- hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}methane- sulfonamide

2-hydroxy-N-{3-[4-({4-[(1- hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}ethane- 1-sulfonamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}oxane- 4-sulfonamide

2-cyclopropyl-N-{3-[4-({4-[(1- hydroxycyclo-propyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]phenyl}ethane-1-sulfonamide

3,3-difluoro-N-{3-[4-({4-[(1- hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- butane-1-carboxamide

1-[(4-{[4-(1H-1,3-benzodiazol-4-yl)-2-chlorophenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-cyclopropyl-2H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-cyclopropyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

N-{4-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- propanecarboxamide

N-{3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-N- methylcyclopropanesulfonamide

N-{3-[4-({4-[(1-methoxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-N- methylcyclopropanesulfonamide

3-cyclopropyl-1-{3-[4-({4-[(1- hydroxycyclo-propyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]phenyl}urea

3-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl N- cyclopropylcarbamate

N-{4-[4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- propanesulfonamide

N-{3-[3-chloro-4-({4-[(1-hydroxycyclo- propyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- propanecarboxamide

N-(3-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclo- pentanecarboxamide

1-(4-{4-[4-(1H-pyrazol-4- yl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

1-{4-[4-(1,2,3,4-tetrahydroisoquinolin- 2-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(1,3-dimethyl-1H-indazol-5- yl)-2-fluorobenzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1-(4-{4-[4-(1-methyl-1H-pyrazol-4- yl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

1-[(2S)-4-[2-fluoro-4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]-2-methyl- piperazine-1-carbonyl]cyclopropan-1-ol

1-{4-[3-chloro-4-(1-methyl-1H-indazol- 6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-{4-[3-chloro-4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-[4-(4-{pyrazolo[1,5-a]pyridin-6- yl}benzoyl)piperazine-1-carbonyl]cyclopropan-1-ol

1-{4-[4-(4-fluoro-2,3-dihydro-1H- indol-1-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(3-methyl-1H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(3-methyl-1H- indazol-7-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(2S)-2-methyl-4-[4-(1-methyl- 1H-indazol-6-yl)benzoyl]piperazine-1-carbonyl]cyclopropan-1-ol

1-{4-[3-chloro-4-(2-methyl-2H- indazol-6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

3,3,3-trifluoro-N-(3-{4-[4-(1- hydroxycyclopropane-carbonyl)piperazine-1- carbonyl]phenyl}phenyl)propane- 1-sulfonamide

1-{4-[2-fluoro-4-(1-methyl-1H- indazol-6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{3,3-dimethyl-4-[4-(1-methyl- 1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-{4-[2,6-difluoro-4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(1-methyl-1H- indazol-6-yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1-amine

1-{4-[3-chloro-4-(6-chloro- 1,3-benzoxazol-2- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(1,3-dimethyl-1H-indazol-5- yl)-2-fluorobenzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

N-(3-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclo- butanesulfonamide

1-{4-[4-(2,3-dihydro-1H-indol- 1-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[3-chloro-4-(1,3-dimethyl-1H- indazol-5-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(2S)-2-methyl-4-[4-(1-methyl- 1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol

1-{4-[2,6-difluoro-4-(2-methyl-2H- indazol-6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-(4-{4-[3-(5-amino-1,2-oxazol-3- yl)phenyl]-2-fluorobenzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

1-[(2S)-2-methyl-4-[4-(2-methyl-2H- indazol-6-yl)benzoyl]piperazine-1-carbonyl]cyclopropan-1-ol

1-cyclobutyl-N-(3-{4-[4-(1- hydroxycyclopropane- carbonyl)piperazine-1-carbonyl]phenyl}phenyl)methane- sulfonamide

1-{4-[2-fluoro-4-(7-fluoro-1H-indazol- 3-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(2S)-4-[4-(6-chloro-1,3-benzoxazol- 2-yl)benzoyl]-2-methylpiperazine-1-carbonyl]cyclopropan-1-ol

1-{4-[4-(1H-indol-1- yl)benzoyl]piperazine- 1-carbonyl}cyclopropan-1-ol

1-{4-[4-(7-fluoro-1H-indazol-3- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(7-fluoro-1,2,3,4- tetrahydroisoquinolin-2-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(2-methyl-2H- indazol-6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(3-amino-1H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(3-amino-1,2-benzoxazol- 5-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(1,3-dimethyl-1H-indazol-5- yl)-2-fluorobenzoyl]piperazine-1-carbonyl}cyclobutan-1-amine

1-{4-[2-fluoro-4-(3-methyl-1H- indazol-6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

ethyl N-(3-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)carbamate

1-{4-[4-(5-chloro-2-methyl-1H-1,3- benzodiazol-7-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[4-(4-{1H,2H,3H,4H,9H-pyrido[3,4- b]indol-2-yl}benzoyl)piperazine-1-carbonyl]cyclopropan-1-ol

1-[(2R,6S)-2,6-dimethyl-4-[4-(1- methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol

1-[4-(2-chloro-4-{3-chloroimidazo[1,2-a]pyridin-2-yl}benzoyl)piperazine-1- carbonyl]cyclopropan-1-ol

1-{4-[4-(4-chloro-2- fluorophenyl)benzoyl]- 3,3-dimethylpiperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-chloro-4-(1-methyl-1H- indazol-6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(2S)-4-[4-(4-chloro-2- fluorophenyl)benzoyl]-2- methylpiperazine-1-carbonyl]cyclopropan-1-ol

1-[(2S)-4-[4-(1,3-dimethyl-1H-indazol- 5-yl)benzoyl]-2-methylpiperazine-1-carbonyl]cyclopropan-1-ol

1-(4-{4-[3-(5-amino-1,2-oxazol-3- yl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

2-(3-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)acetonitrile

N-(3-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}phen- yl)cyclopentanesulfonamide

1-[(3S)-3-methyl-4-[4-(1-methyl-1H- 1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol

1-cyclopropyl-N-(3-{4-[4-(1- hydroxycyclopropane- carbonyl)piperazine-1-carbonyl]phenyl}phenyl)methane- sulfonamide

1-{4-[3-chloro-4-(6-fluoro-1,3- benzoxazol-2-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-chloro-4-(2-methyl-2H- indazol-6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2,6-difluoro-4-(1-methyl-1H- indazol-6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(3R)-3-methyl-4-[4-(1-methyl- 1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol

N-(6-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}-1,2-benzoxazol- 3-yl)cyclopropanecarboxamide

1-[(3R,5S)-3,5-dimethyl-4-[4-(1- methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol

propan-2-yl N-(3-{4-[4-(1- hydroxycyclopropane- carbonyl)piperazine-1-carbonyl]phenyl}phenyl)carbamate

1-{4-[4-(3-amino-1H-indazol- 5-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(2R)-2-methyl-4-[4-(1-methyl- 1H-1,3-benzodiazol-5-yl)benzoyl]piperazine- 1-carbonyl]cyclopropan-1-ol

3,3-difluoro-N-(3-{4-[4-(1- hydroxycyclopropane- carbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclobutane- 1-carboxamide

1-[(2S,6R)-4-[4-(6-fluoro-1,3- benzoxazol-2-yl)benzoyl]-2,6-dimethylpiperazine-1- carbonyl]cyclopropan-1-ol

1-(4-{4-[1-(2-hydroxyethyl)-1H- 1,3-benzodiazol-6-yl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol

1-{4-[4-(1H-1,3-benzodiazol-4- yl)-2-chlorobenzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(5-fluoro-2,3-dihydro-1H- indol-1-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[4-(4-{3-chloroimidazo[1,2- a]pyridin-2-yl}-2-fluorobenzoyl)piperazine- 1-carbonyl]cyclopropan-1-ol

1-{4-[4-(4-chloro-2-fluorophenyl)-2- fluorobenzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[3-chloro-4-(4-chloro-2- fluorophenyl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-chloro-4-(6-chloro- 1,3-benzoxazol-2- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(5-fluoro-2,3- dihydro-1H-isoindol-2- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(3-methyl-1H-indazol- 4-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(6-methoxy-1,3-benzoxazol- 2-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(3-methyl-1H-indazol- 7-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(2R)-4-[4-(4-chloro-2-fluoro- phenyl)benzoyl]-2-methylpiperazine-1-carbonyl]cyclopropan-1-ol

1-(3-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclo- butane-1-carbonitrile

1-{4-[2-fluoro-4-(6-fluoro- 1,3-benzoxazol-2- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[4-(4-{1H,2H,3H,4H,5H- pyrido[4,3-b]indol-2- yl}benzoyl)piperazine-1-carbonyl]cyclopropan-1-ol

1-{4-[4-(2-methyl-1H-indol- 1-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(2S)-2-methyl-4-[4-(1-methyl- 1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-amine

1-{4-[3-fluoro-4-(1-methyl- 1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(1-methyl- 1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl}cyclobutan-1-amine

1-{4-[3-fluoro-4-(1-methyl-1H- indazol-6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(2S)-4-[4-(6-fluoro-1,3- benzoxazol-2-yl)benzoyl]-2-methylpiperazine-1- carbonyl]cyclopropan-1-ol

1-{4-[4-(4-fluoro-2,3-dihydro- 1H-isoindol-2- yl)benzoyl]piperazine-l-carbonyl}cyclopropan-1-ol

1-(4-{3-chloro-4-[3- (cyclopropanesulfonyl)phen-yl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol

1-{4-[4-(7-fluoro-2,3-dihydro- 1H-indol-1-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(3-cyclopropyl-1H-indazol- 6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(6-fluoro-1,3- benzoxazol-2-yl)benzoyl]-3,3-dimethylpiperazine-1- carbonyl}cyclopropan-1-ol

1-{4-[4-(3-methyl-1H-indazol- 1-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(3-methyl-1H- indazol-7-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1-{4-[4-(1-methanesulfonyl-1H- indol-6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(1-methyl-1H-1,3- benzodiazol-5- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1-{4-[4-(2-methyl-2,3-dihydro-1H- indol-1-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(5-fluoro-1H-1,2,3- benzotriazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[3-chloro-4-(5-chloro-2- fluorophenyl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(2S,6R)-4-[4-(4-chloro-2- fluorophenyl)benzoyl]-2,6-dimethylpiperazine-1- carbonyl]cyclopropan-1-ol

N-(3-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)oxane- 4-sulfonamide

1-{4-[4-(1-methyl-1H-indazol- 6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1-{4-[4-(7-methoxy-1,2,3,4- tetrahydroisoquinolin-2-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-(3-{3-fluoro-4-[4-(1- hydroxycyclopropane- carbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclo- propane-1-carbonitrile

1-{4-[2-fluoro-4-(2-methyl-1H- indol-1-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(1H-1,3-benzodiazol-1- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-(3-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclo- propane-1-carbonitrile

1-{4-[2-fluoro-4-(3-methyl-1H- indazol-1-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(1-methyl-1H- indazol-6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

2-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}-1,2,3,4- tetrahydroisoquinoline-7- carbonitrile

1-(4-{4-[1-(2-hydroxyethyl)- 1H-1,3-benzodiazol-5-yl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol

1-[(2R)-4-[4-(6-fluoro-1,3- benzoxazol-2-yl)benzoyl]-2-methylpiperazine-1- carbonyl]cyclopropan-1-ol

1-{4-[4-(1H-indazol-1- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-chloro-4-(5-chloro-2- fluorophenyl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(1,3-dimethyl-1H-indazol-5- yl)-3-fluorobenzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(4-chloro-2- fluorophenyl)benzoyl]-4,7- diazaspiro[2.5]octane-7-carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(7-fluoro-1H- indazol-3-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

6-{1-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]piperidin-4- yl}naphthalene-2-carbonitrile

1-(3-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}phen- yl)imidazolidin-2-one

1-{4-[2,6-difluoro-4-(2-methyl-2H- indazol-6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1,3-dimethyl-5-{4-[4-(oxetane-2- carbonyl)piperazine-1-carbonyl]phenyl}-1H-indazole

1-{4-[2-fluoro-4-(2-methyl-2H- indazol-6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1-(4-{4-[3-(5-amino-1H-1,2,4-triazol- 3-yl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

1-{4-[4-(1-methyl-1H-1,3- benzodiazol-5-yl)benzoyl]-4,7-diazaspiro[2.5]octane-7- carbonyl}cyclopropan-1-ol

1-{4-[4-(2-methyl-1H-indol-3- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(2-methyl-1H-1,3- benzodiazol-5-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(6-fluoro-1,3-benzoxazol- 2-yl)benzoyl]-4,7-diazaspiro[2.5]octane-7- carbonyl}cyclopropan-1-ol

1-{4-[4-(6-fluoro-1-methyl-1H-1,2,3-benzotriazol-5-yl)benzoyl]piperazine- 1-carbonyl}cyclopropan-1-ol

1-{4-[4-(1-methyl-1H-1,3-benzodiazol- 5-yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1-ol

6-chloro-4-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}-2,3-dihydro-1H- 1,3-benzodiazol-2-one

1-(4-{4-[2-(hydroxymethyl)-1H-1,3- benzodiazol-5-yl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

5-{4-[4-(1-aminocyclopropane- carbonyl)piperazine-1-carbonyl]phenyl}-1,2-benzoxazol- 3-amine

1-{4-[4-(2-cyclopropyl-2H-indazol- 5-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(5,6,7,8-tetrahydro- 1,7-naphthyridin-7-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-{4-[4-(3-methyl-1,2,3,4- tetrahydroisoquinolin-2-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-{4-[4-(2,3-dihydro-1H-isoindol-2- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(3R)-4-[4-(4-chloro-2-fluoro- phenyl)benzoyl]-3-methylpiperazine-1-carbonyl]cyclopropan-1-ol

1-[4-(4-{3-methyl-1H-pyrazolo[3,4- b]pyridin-5-yl}benzoyl)piperazine-1-carbonyl]cyclopropan-1-ol

1-{4-[4-(3-methyl-1H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1-{4-[2-fluoro-4-(1-methyl-1H-1,3- benzodiazol-5-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

6-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}-1-methyl-1H- indazol-3-ol

1-{4-[4-(1,2,3,4-tetrahydroquinolin- 1-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(3-methyl-1H-indazol-7- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1-[4-(4-{4H,5H,6H,7H-thieno[3,2- c]pyridin-5-yl}benzoyl)piperazine-1-carbonyl]cyclopropan-1-ol

1-{4-[4-(1-methyl-1H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1-amine

1-(4-{4-[3-(2-amino-1,3-thiazol-4- yl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

1-{4-[4-(1,3-dimethyl-1H-indazol- 5-yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1-amine

1-(4-{4-[3-(cyclopropane- sulfonyl)phenyl]-2-fluorobenzoyl}piperazine-1- carbonyl)cyclopropan-1-ol

1-{4-[4-(6-fluoroquinazolin-2- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

N-(5-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}-1,2-benzoxazol- 3-yl)cyclopropanecarboxamide

4-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}-1-methyl-2,3- dihydro-1H-indol-2-one

1-[(3R)-4-[4-(6-fluoro-1,3- benzoxazol-2-yl)benzoyl]-3-methylpiperazine-1- carbonyl]cyclopropan-1-ol

1-{4-[4-(2-methyl-1H-1,3- benzodiazol-1- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(5-chloro-2-fluoro- phenyl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1-{4-[3-fluoro-4-(2-methyl-2H- indazol-6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

3-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}-N- methylbenzamide

1-(4-{4-[3-(5-amino-1H-pyrazol- 3-yl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

1-[(2S)-2-methyl-4-[4-(5,6,7,8- tetrahydro-1,7-naphthyridin-7-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol

1-[(3S)-4-[4-(4-chloro-2- fluorophenyl)benzoyl]-3- methylpiperazine-1-carbonyl]cyclopropan-1-ol

2-(3-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}phenoxy)- N-methylacetamide

1-{4-[4-(1-cyclopropyl-1H-indazol- 5-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-methyl-5-{4-[4-(oxetane- 2-carbonyl)piperazine-1-carbonyl]phenyl}-1H-1,3- benzodiazole

(1-{4-[4-(1-methyl-1H-1,3- benzodiazol-5-yl)benzoyl]piperazine-1-carbonyl}cyclopropyl)methanol

1-{4-[4-(1-methyl-1H-1,3- benzodiazol-5- yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1-amine

1-[4-(3-chloro-4-{3- chloroimidazo[1,2-a]pyridin-2-yl}benzoyl)piperazine-1- carbonyl]cyclopropan-1-ol

1-[(2R)-2-(hydroxymethyl)-4-[4- (1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol

1-{4-[4-(2,3,4,5-tetrahydro-1H- 3-benzazepin-3- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(2S,6R)-4-[4-(6-fluoro-1,3- benzoxazol-2-yl)benzoyl]-2,6-dimethylpiperazine-1- carbonyl]cyclopropan-1-amine

1-[(2S)-4-[4-(6-fluoro-1,3- benzoxazol-2-yl)benzoyl]-2-methylpiperazine-1- carbonyl]cyclopropan-1-amine

1-(4-{4-[3-(5-methyl-1,3,4-thiadiazol- 2-yl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

1-{4-[4-(3-methyl-2H-indazol- 2-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

2-(3-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)-2- methylpropanenitrile

1-[(2S)-4-{4-[3-(cyclopropane- sulfonyl)phenyl]benzoyl}-2-methylpiperazine-1- carbonyl]cyclopropan-1-ol

1-(3-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)pyrrolidin- 2-one

3-(3-{4-[4-(1-aminocyclo- propanecarbonyl)piperazine-1-carbonyl]-3-fluorophenyl}phenyl)- 1,2-oxazol-5-amine

6-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}-N- methylpyridine-2-carboxamide

1-[(3S)-4-[4-(6-fluoro-1,3- benzoxazol-2-yl)benzoyl]-3-methylpiperazine-1- carbonyl]cyclopropan-1-ol

4-(3-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)oxane- 4-carbonitrile

1-(4-{4-[3-(5-methyl-1,2,4-oxadiazol- 3-yl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

5-(3-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)-5- methylimidazolidine-2,4-dione

1-{4-[2-fluoro-4-(2-methyl-1H- indol-1-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1-{4-[4-(3-amino-1,2-benzoxazol- 6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(2-methyl-2H- indazol-6-yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1-amine

2-(3-{4-[4-(1-hydroxycyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)- 1λ⁶,2-thiazolidine- 1,1-dione

1-{4-[4-(6-chloro-1,3-benzoxazol- 2-yl)-3-fluorobenzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(2,3,4,5-tetrahydro-1H-2- benzazepin-2-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[4-(4-{3-chloroimidazo[1,2- a]pyridin-2-yl}-3-fluorobenzoyl)piperazine-1- carbonyl]cyclopropan-1-ol

1-(3-{4-[4-(1-aminocyclo- propanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclo- propane-1-carbonitrile

1-{4-[3-fluoro-4-(6-fluoro-1,3- benzoxazol-2- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(2-methyl-2H-1,2,3- benzotriazol-5- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(3S)-3-methyl-4-[4-(1-methyl- 1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-amine

EXAMPLES

The following are illustrative, but non-limiting, examples of certainembodiments of the present invention. The synthetic schemes arepresented for the synthesis of certain compounds herein disclosed. Theprocess and results for the assays testing FASN inhibition and effectson cancer cell line proliferation are also described.

Definitions Used in the Following Schemes and Elsewhere Herein are

-   -   Ar-B(OH)₂ aryl boronic acid    -   Ar-B(OR)₂ aryl boronic ester    -   Ar-X aryl halide    -   Atm atmosphere    -   BOP ammonium 4-(3-(pyridin-3-1methyl)ureido)benzenesulfinate    -   δ chemical shift (ppm)    -   CbzCl benzyl chloroformate    -   DCM dichloromethane or methylene chloride    -   DDQ 2,3-Dichloro-5,6-dicyano-p-benzoquinone    -   DIEA N,N-diisopropylethylamine    -   DMA N,N-dimethylacetamide    -   DMF N,N-dimethylformamide    -   DMSO dimethylsulfoxide    -   EDC N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine        hydrochloride    -   ES electrospray    -   Et₃N trithylamine    -   EtOAc ethyl acetate    -   EtOH ethanol    -   EtN(i-Pr)2 diisopropylethyl amine    -   equiv equivalents    -   FCC flash column chromatography    -   GF/F glass microfiber filter    -   ¹H NMR proton nuclear magnetic resonance    -   HCl hydrogen chloride    -   HOAc acetic acid    -   HATU        2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium        hexafluorophosphate    -   HBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate    -   HOBt 1H-benzo[d][1,2,3]triazol-1-ol hydrate    -   HPLC high pressure liquid chromatography    -   i-PrOH isopropanol    -   (i-Pr₂)NEt N,N-Diisopropylethylamine    -   LC-MS liquid chromatography/mass spectrometry    -   LiOH lithium hydroxide    -   (M+1) mass+1    -   m/z mass to charge ratio    -   MS mass spectrometry or molecular sieves    -   N₂ nitrogen    -   NaH sodium hydride    -   nm nanometer    -   NaOH sodium hydroxide    -   NaHCO₃ sodium bicarbonate    -   MeI methyl iodide    -   MeOH methanol    -   MeSO₃H methane sulfonic acid    -   MgSO₄ magnesium sulfate    -   mmol millimoles    -   μwave microwave    -   Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium    -   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium    -   Pd(dppf)Cl₂        [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)    -   PTLC preparative thin layer chromatography    -   RCO₂H 1-hydroxycyclopropanecarboxylic acid    -   r.t. or RT room temperature    -   SOCl₂ thionyl chloride    -   TEA triethylamine    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   TLC thin layer chromatography    -   UV ultraviolet    -   X-Phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl        Materials

Unless otherwise noted, all materials were obtained from commercialsuppliers and were used without further purification. Anhydrous solventswere obtained from Sigma-Aldrich (Milwaukee, Wis.) and used directly.All reactions involving air- or moisture-sensitive reagents wereperformed under a nitrogen atmosphere. Purity and low resolution massspectral data were measured using either: (1) Waters Acquity ultraperformance liquid chromatography (UPLC) system (Waters Acquity UPLCwith Sample Organizer and Waters Micromass ZQ Mass Spectrometer) with UVdetection at 220 nm and a low resonance electrospray positive ion mode(ESI) (Column: Acquity UPLC BEH C₁₈ 1.7 μm 2.1×50 mm; gradient: 5-100%Solvent B (95/5/0.09%: Acetonitrile/Water/Formic Acid) in Solvent A(95/5/0.1%: 10 mM Ammonium Formate/Acetonitrile/Formic Acid) for 2.2 minthen 100-5% Solvent B in Solvent A for 0.01 min then hold at 5% SolventB in Solvent A for 0.29 min) or (2) Waters HT2790 Alliance highperformance liquid chromatography (HPLC) system (Waters 996 PDA andWaters ZQ Single Quad Mass Spectrometer) with UV detection at 220 nm and254 nm and a low resonance electrospray ionization (positive/negative)mode (ESI) (Column: XBridge Phenyl or C18, 5 m 4.6×50 mm; gradient:5-95% Solvent B (95% methanol/5% water with 0.1% Formic Acid) in SolventA (95% water/5% methanol with 0.1% Formic Acid) for 2.5 min then hold at95% Solvent B in Solvent A for 1 min).

General Methods for Compound Synthesis:

Step 1. tert-butyl 4-(4-bromobenzoyl)piperazine-1-carboxylate(Intermediate 1)

N,N-Diisopropylethylamine (28.6 mL, 164 mmol) was added to a 0° C.solution of tert-butyl piperazine-1-carboxylate (10.18 g, 54.7 mmol) and4-bromobenzoyl chloride (12.0 g, 54.7 mmol) in DMF (80 mL), and thereaction mixture stirred at rt for 6 h. Water was added and theresulting mixture was stirred overnight and then filtered and dried toafford tert-butyl 4-(4-bromobenzoyl)piperazine-1-carboxylate (19.388 g,52.5 mmol, 96% yield) as an off-white solid. MS (ESI, pos. ion) m/z:369, 371 (M+1).

Step 2. tert-butyl4-(4′-chloro-2′-fluorobiphenylcarbonyl)piperazine-1-carboxylate

Tetrakis(triphenylphosphine)palladium (0) (1.565 g, 1.354 mmol) wasadded to a mixture of tert-butyl4-(4-bromobenzoyl)piperazine-1-carboxylate (5.00 g, 13.54 mmol),4-chloro-2-fluorophenylboronic acid (2.95 g, 16.93 mmol), and sodiumcarbonate (5.74 g, 54.2 mmol) in 1,4-dioxane (50 mL) and water (10 mL).The mixture stirred at 70° C. for 5 h. The reaction mixture was filteredthrough Celite and concentrated to afford an orange oil. This materialwas purified via column chromatography on silica gel (Biotage 100 gcolumn, gradient elution with 0-50% ethyl acetate-hexane) to affordtert-butyl4-(4′-chloro-2′-fluorobiphenylcarbonyl)piperazine-1-carboxylate (5.508g, 13.15 mmol, 97% yield) as a tan solid. MS (ESI, pos. ion) m/z: 419(M+1).

Step 3. (4′-chloro-2′-fluorobiphenyl-4-yl)(piperazin-1-yl)methanone2,2,2-trifluoroacetate

Trifluoroacetic acid (20.0 mL, 260 mmol) was added to a solution oftert-butyl4-(4′-chloro-2′-fluorobiphenylcarbonyl)piperazine-1-carboxylate (11.35g, 27.1 mmol) in dichloromethane (100 mL) and the solution stirred at rtfor 1.5 h. The reaction mixture was concentrated and the residue wastriturated with diethyl ether to afford(4′-chloro-2′-fluorobiphenyl-4-yl)(piperazin-1-yl)methanone2,2,2-trifluoroacetate (12.02 g, 27.8 mmol, 100% yield) as a tan solid.MS (ESI, pos. ion) m/z: 319 (M+1).

Step 4.(4′-chloro-2′-fluorobiphenyl-4-yl)(4-(1-hydroxycyclopropanecarbonyl)piperazin-1-yl)methanone

N,N-Diisopropylethylamine (9.12 mL, 52.2 mmol) was added to a solutionof (4′-chloro-2′-fluorobiphenyl-4-yl)(piperazin-1-yl)methanone2,2,2-trifluoroacetate (5.647 g, 13.05 mmol),1-hydroxycyclopropanecarboxylic acid (1.332 g, 13.05 mmol), and0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(7.42 g, 19.57 mmol) in DMF (50.0 mL), and the reaction mixture stirredat rt for 18 h. The reaction mixture was partitioned between ethylacetate and water. The organic phase was washed with water and brine,dried over anhydrous sodium sulfate, filtered, and concentrated toafford a yellow oil. This material was purified via columnchromatography on silica gel (Biotage 100 g column, gradient elutionwith 0-5% methanol-ethyl acetate) to afford an off-white solid which wasfurther purified via column chromatography on silica gel (Biotage 100 gcolumn, gradient elution with 0-10% methanol-dichloromethane) to afford(4′-chloro-2′-fluorobiphenyl-4-yl)(4-(1-hydroxycyclopropanecarbonyl)piperazin-1-yl)methanone(1.554 g, 3.86 mmol, 30% yield) as a white solid. MS (ESI, pos. ion)m/z: 403 (M+1).

Step 1. (4-bromophenyl)(piperazin-1-yl)methanone 2,2,2-trifluoroacetate

Trifluoroacetic acid (5.0 mL, 64.9 mmol) was added to a solution oftert-butyl 4-(4-bromobenzoyl)piperazine-1-carboxylate (2.00 g, 5.42mmol) in dichloromethane (25.0 mL), and the solution stirred at rt for 2h. The reaction mixture was concentrated and the residue was trituratedwith diethyl ether to afford (4-bromophenyl)(piperazin-1-yl)methanone2,2,2-trifluoroacetate. (1.992 g, 5.20 mmol, 96% yield) as a whitesolid. MS (ESI, pos. ion) m/z: 269, 271 (M+1).

Step 2.(4-(4-bromobenzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

N,N-Diisopropylethylamine (0.46 mL, 2.6 mmol) was added to a solution of(4-bromophenyl)(piperazin-1-yl)methanone 2,2,2-trifluoroacetate (0.250g, 0.652 mmol), 1-hydroxycyclopropanecarboxylic acid (0.067 g, 0.652mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.371 g, 0.979 mmol) in DMF (5.0 mL), and thereaction mixture stirred at rt for 18 h. The reaction mixture waspartitioned between ethyl acetate and water. The organic phase waswashed with brine, dried over anhydrous sodium sulfate, filtered, andconcentrated to afford an orange oil. This material was purified viacolumn chromatography on silica gel (Biotage 25 g column, gradientelution with 0-5% methanol-dichloromethane) to afford(4-(4-bromobenzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (0.195g, 0.552 mmol, 85% yield) as a light orange solid. MS (ESI, pos. ion)m/z: 353, 355 (M+1).

Step 3.(4-(4-(benzo[d]thiazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

Tetrakis(triphenylphosphine)palladium(0) (0.016 g, 0.014 mmol) was addedto a mixture of(4-(4-bromobenzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (0.050g, 0.142 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (0.055g, 0.212 mmol), and sodium carbonate (0.060 g, 0.566 mmol) in dioxane(1.5 mL) and water (0.30 mL). The mixture stirred in the microwave at50° C. for 1 h. The reaction mixture was filtered through Celite andconcentrated to afford a yellow oil. This material was purified viacolumn chromatography on silica gel (Biotage 25 g column, gradientelution with 0-5% methanol-ethyl acetate) to afford(4-(4-(benzo[d]thiazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone(0.020 g, 0.049 mmol, 35% yield) as an off-white solid. MS (ESI, pos.ion) m/z: 408 (M+1).

Step 1. tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid(15 g, 60.5 mmol), tert-butyl piperazine-1-carboxylate (11.26 g, 60.5mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (4.63 g, 30.2 mmol),N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (12.75 g, 66.5 mmol), and triethylamine (33.7 mL, 242mmol) in dichloromethane (180 mL) was stirred at room temperatureovernight. The reaction mixture was washed with saturated aqueous sodiumbicarbonate solution (75 mL), 0.5 M HCl solution (75 mL), and again withsaturated aqueous sodium bicarbonate solution (75 mL). The combinedorganic phases were concentrated and the resulting solid was slurried ina solution of 1:1 methyl tert-butyl ether/hexane (200 mL). The materialwas filtered and dried to afford tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate(20.03 g, 48.1 mmol, 80%). MS (ESI, pos. ion) m/z: 417 (M+1).

Step 2 (Pd(PPh₃)₄). tert-butyl4-(4-(1H-benzo[d]imidazol-2-yl)benzoyl)piperazine-1-carboxylate

Tetrakis(triphenylphosphine)palladium(0) (0.028 g, 0.024 mmol) was addedto a mixture of tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate(0.050 g, 0.120 mmol), 2-bromo-1H-benzo[d]imidazole (0.035 g, 0.180mmol), and sodium carbonate (0.051 g, 0.480 mmol) in dioxane (1.5 mL)and water (0.30 mL). The mixture stirred in the microwave at 50° C. for3 h. The reaction mixture was filtered through Celite and concentrated.The residue was purified via column chromatography on silica gel(Biotage 10 g column, gradient elution with 0-50% ethyl acetate-hexane)to afford tert-butyl4-(4-(1H-benzo[d]imidazol-2-yl)benzoyl)piperazine-1-carboxylate (0.027g, 0.066 mmol, 55% yield) as an off-white solid. MS (ESI, pos. ion) m/z:407 (M+1).

Step 2 (X-Phos). tert-butyl4-(4-(pyrazolo[1,5-a]pyridin-2-yl)benzoyl)piperazine-1-carboxylate

A mixture of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate(0.100 g, 0.240 mmol), 2-chloropyrazolo[1,5-a]pyridine (0.046 g, 0.300mmol), tris(dibenzylideneacetone)dipalladium (0.011 g, 0.012 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos, 0.011 g,0.024 mmol), and cesium carbonate (0.235 g, 0.721 mmol) in dioxane (2.5mL) and water (0.50 mL) was stirred in the microwave at 80° C. for 1 h.The reaction mixture was filtered through Celite and concentrated toafford a yellow-brown oil. This material was purified via columnchromatography on silica gel (Biotage 25 g column, gradient elution with0-50-100% ethyl acetate-hexane) to afford tert-butyl4-(4-(pyrazolo[1,5-a]pyridin-2-yl)benzoyl)piperazine-1-carboxylate(0.056 g, 0.138 mmol, 57% yield) as an off-white solid. MS (ESI, pos.ion) m/z: 407 (M+1).

Step 3. (4-(1H-benzo[d]imidazol-2-yl)phenyl)(piperazin-1-yl)methanone2,2,2-trifluoroacetate (Intermediate 2)

Trifluoroacetic acid (1.0 mL, 12.98 mmol) was added to a solution oftert-butyl4-(4-(1H-benzo[d]imidazol-2-yl)benzoyl)piperazine-1-carboxylate (0.027g, 0.066 mmol) in dichloromethane (3.0 mL), and the solution stirred atrt for 1.5 h. The reaction mixture was concentrated and the residue wastriturated with diethyl ether and filtered to afford(4-(1H-benzo[d]imidazol-2-yl)phenyl)(piperazin-1-yl)methanone2,2,2-trifluoroacetate (0.028 g, 0.067 mmol, 100% yield) as a brownfilm. MS (ESI, pos. ion) m/z: 307 (M+1).

Step 4.(4-(4-(1H-benzo[d]imidazol-2-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

DIEA (0.047 mL, 0.266 mmol) was added to a solution of(4-(1H-benzo[d]imidazol-2-yl)phenyl)(piperazin-1-yl)methanone2,2,2-trifluoroacetate (0.028 g, 0.067 mmol),1-hydroxycyclopropanecarboxylic acid (7.14 mg, 0.070 mmol), andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(0.038 g, 0.100 mmol) in DMF (1.0 mL), and the reaction mixture stirredat rt for 20 h. Water was added and the mixture was partitioned betweenethyl acetate and water. The aqueous phase was separated and extractedwith dichloromethane. The combined organic phases were washed withbrine, dried over anhydrous sodium sulfate, and filtered to afford abrown oil. This material was purified via column chromatography onsilica gel (Biotage 10 g column, gradient elution with 0-5%methanol-ethyl acetate) to afford(4-(4-(1H-benzo[d]imidazol-2-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone(0.004 g, 10.24 μmol, 15% yield) as a white solid. MS (ESI, pos. ion)m/z: 391 (M+1).

Step 1. Methyl 4-(benzo[d]oxazol-2-yl)benzoate

Thionyl chloride (10 mL, 137 mmol) was added to mono-methylterephthalate (5.00 g, 27.8 mmol). A drop of DMF was added, and themixture was heated at 80° C. for 2 h. The excess thionyl chloride wasremoved, and the residue was treated with 2-aminophenol (3.03 g, 27.8mmol) and dioxane (60 mL). Methanesulfonic acid (5.59 mL, 86 mmol) wasadded and the reaction mixture was heated at reflux for 18 h. Thesolution was concentrated and the residue was partitioned betweendichloromethane and satd. aq. sodium bicarbonate solution. The aqueousphase was separated and washed with dichloromethane and the combinedorganic phases were washed with brine, filtered, and concentrated toafford a brown solid. This material was triturated with methanol,filtered, and dried to afford methyl 4-(benzo[d]oxazol-2-yl)benzoate(4.827 g, 19.06 mmol, 69% yield) as an off-white solid. MS (ESI, pos.ion) m/z: 254 (M+1).

Step 2 (LiOH). 4-(Benzo[d]oxazol-2-yl)benzoic acid

Lithium hydroxide (0.894 g, 37.3 mmol) was added to a solution of methyl4-(benzo[d]oxazol-2-yl)benzoate (4.728 g, 18.67 mmol) in THF (25 mL),Methanol (25 mL), and Water (25 mL), and the mixture stirred at rt for18 h. The reaction mixture was concentrated and the aqueous solution wasacidified to pH=5-6 with 1 N aq HCl solution. The resulting off-whiteprecipitate was filtered and dried to afford4-(benzo[d]oxazol-2-yl)benzoic acid (3.846 g, 16.08 mmol, 86% yield) asan off-white solid. MS (ESI, pos. ion) m/z: 240 (M+1).

Step 2 (NaOH). 4-(5-cyanobenzo[d]oxazol-2-yl)benzoic acid

Sodium hydroxide (0.067 g, 1.675 mmol) was added to a solution of methyl4-(5-cyanobenzo[d]oxazol-2-yl)benzoate (0.233 g, 0.837 mmol) in THF (4.0mL) and water (2.00 mL), and the mixture stirred at rt for 18 h. Thereaction mixture was concentrated and the aqueous solution was acidifiedto pH=5-6 with 1 N aq HCl solution. The resulting off-white precipitatewas filtered and dried to afford 4-(5-cyanobenzo[d]oxazol-2-yl)benzoicacid (0.176 g, 0.666 mmol, 80% yield) as an off-white solid. MS (ESI,pos. ion) m/z: 265 (M+1).

Step 3. tert-Butyl4-(4-(benzo[d]oxazol-2-yl)benzoyl)piperazine-1-carboxylate

Thionyl chloride (25.0 mL, 343 mmol) was added to4-(benzo[d]oxazol-2-yl)benzoic acid (3.5 g, 14.63 mmol). A drop of DMFwas added and the mixture was heated at 80° C. for 1 h. The excessthionyl chloride was removed and DMF (40 mL) was added. tert-Butylpiperazine-1-carboxylate (2.72 g, 14.63 mmol) andN,N-diisopropylethylamine (7.67 mL, 43.9 mmol) were added, and thereaction mixture stirred at rt for 1.5 h. Water was added and theresulting mixture was stirred and then filtered and dried to affordtert-butyl 4-(4-(benzo[d]oxazol-2-yl)benzoyl)piperazine-1-carboxylate(5.006 g, 12.29 mmol, 84% yield) as a light tan solid. MS (ESI, pos.ion) m/z: 408 (M+1).

Step 4. (4-(Benzo[d]oxazol-2-yl)phenyl)(piperazin-1-yl)methanone2,2,2-trifluoroacetate

Trifluoroacetic acid (10.0 mL, 130 mmol) was added to a solution oftert-butyl 4-(4-(benzo[d]oxazol-2-yl)benzoyl)piperazine-1-carboxylate(5.006 g, 12.29 mmol) in dichloromethane (50 mL), and the solutionstirred at rt for 5 h. The reaction mixture was concentrated and theresidue was triturated with diethyl ether and filtered to afford(4-(benzo[d]oxazol-2-yl)phenyl)(piperazin-1-yl)methanone2,2,2-trifluoroacetate (5.501 g, 13.06 mmol, 100% yield) as an off-whitesolid. MS (ESI, pos. ion) m/z: 308 (M+1).

Step 5 (acid chloride coupling).(4-(4-(Benzo[d]oxazol-2-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

Thionyl chloride (2.0 mL, 27.4 mmol) was added to1-hydroxycyclopropanecarboxylic acid (0.115 g, 1.123 mmol). A drop ofDMF was added and the mixture was heated at 80° C. for 1 h. The excessthionyl chloride was removed to afford a brown oil. This material wasadded to a solution of(4-(benzo[d]oxazol-2-yl)phenyl)(piperazin-1-yl)methanone2,2,2-trifluoroacetate (0.338 g, 0.802 mmol) andN,N-diisopropylethylamine (0.70 mL, 4.01 mmol) in dichloromethane (3.0mL). The reaction mixture stirred at rt for 2 h. The mixture wasconcentrated and the residue was purified via column chromatography onsilica gel (Biotage 25 g column, gradient elution with 0-5%methanol-ethyl acetate) to afford(4-(4-(benzo[d]oxazol-2-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)-methanone(0.208 g, 0.531 mmol, 66% yield) as a pink solid. MS (ESI, pos. ion)m/z: 392 (M+1).

Step 5 (HBTU coupling).(4-(4-(5-Chlorobenzo[d]oxazol-2-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

N,N-Diisopropylethylamine (0.376 mL, 2.150 mmol) was added to a solutionof (4-(5-chlorobenzo[d]oxazol-2-yl)phenyl)(piperazin-1-yl)methanone2,2,2-trifluoroacetate (0.245 g, 0.537 mmol),1-hydroxycyclopropanecarboxylic acid (0.058 g, 0.564 mmol), andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU, 0.306 g, 0.806 mmol) in DMF (5.0 mL), and the reaction mixturestirred at rt for 20 h. Water was added and the resulting precipitatewas filtered and dried. This material was purified via columnchromatography on silica gel (Biotage 50 g column, gradient elution with0-5% methanol-ethyl acetate) to afford(4-(4-(5-chlorobenzo[d]oxazol-2-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone(0.136 g, 0.319 mmol, 59% yield) as an off-white solid. MS (ESI, pos.ion) m/z: 426 (M+1).

Preparation of(4-(2-chloro-4-(quinolin-6-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

4-Bromo-2-chlorobenzoic acid (0.2 M in 1,4-dioxane, 180 μL, 0.036 mmol)was added to a solution of tert-butyl piperazine-1-carboxylate (0.2 Msolution in 1,4-dioxane with 5% N,N-diisopropylethylamine, 150 μL, 0.03mmol). (Benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophophate (BOP, 0.5 M solution in 1,2-dichloroethane, 72 μL,0.036 mmol) was added, and the resulting mixture was put on a shaker atrt for 2 hour. Quinolin-6-ylboronic acid (0.2 M solution in 1,4-dioxane,225 μL, 0.045 mmoL) and potassium phosphate (1 M aqueous, 150 μL, 0.15mmol) were added. Tetrakis(triphenylphosphine)palladium (0) solution(0.02 M toluene, 75 μL, 1.5 μmol) was then added under a nitrogenatmosphere, and the resulting mixture was put on shaker in a glove boxunder nitrogen atmosphere and heated at 80° C. overnight. After beingcooled to rt, the mixture was diluted with brine (0.30 mL) and ethylacetate (0.5 mL). The organic layer was separated and the aqueous layerwas extracted again with ethyl acetate (0.6 mL). The combined organiclayers were dried down and the residue was re-dissolved in methanol (400μL). HCl solution (4 N in 1,4-dioxane, 75 μL, 0.2 mmol) was added, andthe mixture was heated on a shaker at 50° C. for 1 hour. The reactionmixture was dried down in vacuo and the residue was re-dissolved in asolution of 10% N,N-diisopropylethylamine in dimethylacetamide (200 μL).1-Hydroxycyclopropanecarboxylic acid (0.2 M in 1,4-dioxane, 225 μL,0.045 mmol) was added followed by BOP solution (0.5 M in 1,2-DCE, 90 μL,0.045 mmol). The mixture was put on a shaker at rt for 2 hour. Thereaction mixture was then diluted with sodium hydroxide solution (1 N inbrine, 0.45 mL) and ethyl acetate (0.5 mL). The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (0.6mL). The combined organic layers were concentrated and the residue waspurified by high performance liquid chromatography (WatersAutopurification MS-directed HPLC prep fraction collection with thefollowing conditions: Column:Waters XBridge OBD C18, 5 μm, 19×50 mm;flow rate 20 mL/min; mobile phase, water with 0.1% ammonium hydroxide(A) and methanol with 0.1% ammonium hydroxide(B) running the followinggradient 0 to 2 mins (15% B), 2 to 6 mins (15-100% B); Detector ZQ MassDetector in electrospray ionization mode) to afford(4-(2-chloro-4-(quinolin-6-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone(5.9 mg, 14 μmol, 45% yield). MS (ESI, pos. ion) m/z: 436 (M+1).

Step 1. tert-butyl4-(4-(benzo[d]thiazol-2-yl)benzoyl)piperazine-1-carboxylate

Tetrakis(triphenylphosphine)palladium(0) (0.313 g, 0.271 mmol) was addedto a mixture of tert-butyl 4-(4-bromobenzoyl)piperazine-1-carboxylate(1.00 g, 2.71 mmol), 2-(tributylstannyl)benzo[d]thiazole (1.00 mL, 2.84mmol), lithium chloride (0.230 g, 5.42 mmol), and copper(I) iodide(0.026 g, 0.135 mmol) in DMF (25 mL). The mixture stirred at 80° C. for2 h and then at 90° C. for 8 h. The reaction mixture was filteredthrough Celite and the filtrate was partitioned between dichloromethaneand water. The organic phase was separated and washed with brine, driedover anhydrous sodium sulfate, filtered, and concentrated to afford anorange oil. This material was purified via column chromatography onsilica gel (Biotage 50 g column, gradient elution with 0-50% ethylacetate-hexane) to afford tert-butyl4-(4-(benzo[d]thiazol-2-yl)benzoyl)piperazine-1-carboxylate (0.586 g,1.384 mmol, 51% yield) as a brown solid. MS (ESI, pos. ion) m/z: 424(M+1).

Step 2. (4-(benzo[d]thiazol-2-yl)phenyl)(piperazin-1-yl)methanone2,2,2-trifluoroacetate

Trifluoroacetic acid (1.00 mL, 13.0 mmol) was added to a solution oftert-butyl 4-(4-(benzo[d]thiazol-2-yl)benzoyl)piperazine-1-carboxylate(0.586 g, 1.38 mmol) in dichloromethane (5.0 mL), and the solutionstirred at rt for 3 h. The reaction mixture was concentrated and theresidue was triturated with diethyl ether and filtered to afford(4-(benzo[d]thiazol-2-yl)phenyl)(piperazin-1-yl)methanone2,2,2-trifluoroacetate (0.542 g, 1.239 mmol, 90% yield) as a tan solid.MS (ESI, pos. ion) m/z: 324 (M+1).

Step 3.(4-(4-(benzo[d]thiazol-2-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

N,N-Diisopropylethylamine (0.87 mL, 5.0 mmol) was added to a solution of(4-(benzo[d]thiazol-2-yl)phenyl)(piperazin-1-yl)methanone2,2,2-trifluoroacetate (0.542 g, 1.239 mmol),1-hydroxycyclopropanecarboxylic acid (0.133 g, 1.301 mmol), and0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(0.705 g, 1.859 mmol) in DMF (5.0 mL), and the reaction mixture stirredat rt for 16 h. Water was added and the resulting precipitate wasfiltered and dried. This material was purified via column chromatographyon silica gel (Biotage 50 g column, gradient elution with 0-5%methanol-ethyl acetate) to afford(4-(4-(benzo[d]thiazol-2-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone(0.235 g, 0.577 mmol, 47% yield) as an off-white solid. MS (ESI, pos.ion) m/z: 408 (M+1).

Preparation of5-(4-(4-(1-hydroxycyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-1H-indole-3-carbonitrile

To a solution of tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate(0.2 M in 1,4-dioxane, 100 μL, 0.02 mmol), was added5-bromo-1H-indole-3-carbonitrile (0.2 M in 1,4-dioxane, 100 μL, 0.02mmol) and potassium phosphate solution (1 M aqueous, 100 μL, 0.1 mmol).The mixture was bubbled with nitrogen andtetrakis(triphenylphosphine)palladium (0) (0.02 M in toluene, 50 μL, 1μmol) was added. The resulting mixture was put on a shaker in a glovebox under nitrogen atmosphere and heated at 80° C. overnight. Afterbeing cooled to rt, the mixture was diluted with 0.35 mL of brine and0.5 mL of ethyl acetate. The organic layer was separated and the aqueouslayer was extracted again with ethyl acetate (0.6 mL). The combinedorganic layers were concentrated and the residue was dissolved in 200 μLof methanol. HCl solution (50 μL, 4 N in 1,4-dioxane, 0.2 mmol) wasadded. The mixture was put on a shaker at 50° C. for 1 hour. Thereaction mixture was concentrated in vacuo and the residue was dissolvedin a solution of 10% N,N-diisopropylethylamine in dimethylacetamide (200μL). 1-Hydroxycyclopropanecarboxylic acid (0.2 M in 1,4-dioxane, 120 μL,0.024 mmol) was added, followed by BOP solution (0.5 M in1,2-dichloroethane, 48 μL, 0.024 mmol). The mixture was put on a shakerat rt for 2 hour. The reaction mixture was then diluted with 0.45 mL of1N NaOH in brine and 0.5 mL of ethyl acetate. The organic layer wasseparated and the aqueous layer was extracted again with ethyl acetate(0.6 mL). The combined organic layers were concentrated and the residuewas purified by HPLC:Water Autopurification MS-directed HPLC prepfraction collection with the following conditions Column, Waters XBridgeOBD C18, 5 μm, 19×50 mm; flow rate 20 ml/min; mobile phase, water with0.1% ammonium hydroxide (A) and methanol with 0.1% ammonium hydroxide(B)running the following gradient 0 to 2 mins (15% B), 2 to 6 mins (15-100%B); Detector ZQ Mass Detector in electrospray ionization mode.5-(4-(4-(1-Hydroxycyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-1H-indole-3-carbonitrile(3.5 mg, 8.4 μmol, 42% yield) was obtained. MS (ESI, pos. ion) m/z: 415(M+1).

1-(4-(biphenylcarbonyl)paiperazin-1-yl)-2-methoxy-2-methylpropan-1-one

Sodium hydride (9.08 mg, 0.227 mmol) was added to a solution of1-(4-(biphenylcarbonyl)piperazin-1-yl)-2-hydroxy-2-methylpropan-1-one(32 mg, 0.091 mmol) in DMF (4 mL). After stirring at rt for 30 min,methyl iodide (0.028 mL, 0.454 mmol) was added. The mixture was stirredat rt overnight. The mixture was concentrated and the residue waspurified via preparative reversed phase HPLC (20 mL/min, 10 min gradient15%-85% CH₃CN, 0.01% HCO₂H on an XTerra Prep MS C18 OBD 5 μM, 19×100 mmcolumn) to afford1-(4-(biphenylcarbonyl)piperazin-1-yl)-2-methoxy-2-methylpropan-1-one(12.2 mg, 37%). MS (ESI, pos. ion) m/z: 367 (M+1).

Preparation of(4-(2-chloro-4-(quinolin-6-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

To a solution of tert-butyl piperazine-1-carboxylate (0.2 M 1,4-dioxanewith 5% N,N-diisopropylethylamine, 150 μL, 0.03 mmol), was added4-phenoxybenzoic acid (0.2 M 1,4-dioxane, 150 μL, 0.03 mmol), followedby (benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophophate solution (BOP, 0.5 M in 1,2-dichloroethane, 66 μL,0.033 mmol). The resulting mixture was put on a shaker at roomtemperature for 2 hours. Hydrochloric acid solution (4 N in 1,4-dioxane,75 μL) was added and the mixture was put on a shaker at 50° C. for 1hour. After being cooled to room temperature, the mixture wasconcentrated, and the residue was re-dissolved in a solution of 10%diisopropylethyl amine in dimethylacetamide (200 μL).1-Hydroxycyclopropanecarboxylic acid (0.2 M 1,4-dioxane, 180 μL, 0.036mmol) was added to the mixture, followed by BOP solution (0.5 M in1,2-dichloroethane, 72 μL, 0.036 mmol). The mixture was put on a shakerat room temperature for 2 hours. The reaction mixture was then dilutedwith sodium hydroxide solution (1 N in brine, 0.45 mL) and ethyl acetate(0.5 mL). The organic layer was separated and the aqueous layer wasextracted with ethyl acetate (0.6 mL). The combined organic layers wereconcentrated and the residue was purified by high performance liquidchromatography (Waters Autopurification MS-directed HPLC prep fractioncollection with the following conditions: Column:Waters XBridge OBD C18,5 μm, 19×50 mm; flow rate 20 mL/min; mobile phase, water with 0.1%ammonium hydroxide (A) and methanol with 0.1% ammonium hydroxide(B)running the following gradient 0 to 2 mins (15% B), 2 to 6 mins (15-100%B); Detector ZQ Mass Detector in electrospray ionization mode) to afford(4-(2-chloro-4-(quinolin-6-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone(4.1 mg, 11 μmol, 37% yield). MS (ESI, pos. ion) m/z: 367 (M+1).

Step 1. tert-Butyl4-(3-chloro-4-(1H-indol-5-yl)benzoyl)piperazine-1-carboxylate

To a solution of tert-butyl4-(4-bromo-3-chlorobenzoyl)piperazine-1-carboxylate (505 mg, 1.25 mmol)in 1,4-dioxane (9 mL) was added5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (365 mg, 1.5mmol), potassium phosphate (1.06 g, 5 mmol) and water (3 mL). Themixture was bubbled with nitrogen andtetrakis(triphenylphosphine)palladium (0) (72.2 mg, 0.063 mmol) wasadded. The mixture was sealed and heated at 80° C. overnight. Afterbeing cooled to rt, the mixture was diluted with water (10 mL) and ethylacetate (20 mL). The organic layer was separated and the aqueous layerwas extracted with ethyl acetate (20 mL). The combined organic layerswere concentrated to yield tert-butyl4-(3-chloro-4-(1H-indol-5-yl)benzoyl)piperazine-1-carboxylate (578 mg,1.31 mmol, 100% yield). The crude product was used without furtherpurification. MS (ESI, pos. ion) m/z: 440 (M+1).

Step 2.(4-(3-chloro-4-(1-isopropyl-1H-indol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

To a vial charged with sodium hydride (60% in mineral oil, 1.6 mg, 0.040mmol) and DMF (0.1 mL), was added tert-butyl4-(3-chloro-4-(1H-indol-5-yl)benzoyl)piperazine-1-carboxylate (0.2 M inDMF, 0.1 mL, 0.02 mmol), followed by 2-iodopropane (0.2 M in DMF, 0.2mL, 0.04 mmol). The resulting mixture was put on a shaker for 30 min. atroom temperature. The mixture was then diluted with water and ethylacetate. The organic layer was separated and the aqueous layer wasextracted with ethyl acetate. The combined organic layers wereconcentrated in vacuo. The residue was dissolved in methanol (0.3 mL)and HCl solution (4 N 1,4-dioxane, 50 μL) was added. The mixture was puton a shaker at 50° C. for 1 hour. After being cooled to roomtemperature, the mixture was concentrated. The residue was dissolved ina solution of 5% N,N-diisopropylethylamine in dimethylacetamide (0.2 mL)and 1-hydroxycyclopropanecarboxylic acid (0.2 M 1,4-dioxane, 120 μL,0.024 mmol) was added, followed by BOP solution (0.5 M in1,2-dichloroethane, 48 μL, 0.024 mmol). The mixture was put on a shakerat room temperature for 2 hours. The reaction mixture was diluted withsodium hydroxide solution (1 N in brine, 0.45 mL) and ethyl acetate (0.5mL). The organic layer was separated and the aqueous layer was extractedwith ethyl acetate (0.6 mL). The combined organic layers wereconcentrated and the residue was purified by high performance liquidchromatography (Waters Autopurification MS-directed HPLC prep fractioncollection with the following conditions: Column:Waters XBridge OBD C18,5 μm, 19×50 mm; flow rate 20 mL/min; mobile phase, water with 0.1%ammonium hydroxide (A) and methanol with 0.1% ammonium hydroxide(B)running the following gradient 0 to 2 mins (15% B), 2 to 6 mins (15-100%B); Detector ZQ Mass Detector in electrospray ionization mode) to afford(4-(3-chloro-4-(1-isopropyl-1H-indol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone(2.2 mg, 4.7 μmol, 24% yield). MS (ESI, pos. ion) m/z: 466 (M+1).

Step 1. tert-Butyl4-(3′-amino-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate

To a solution of tert-butyl piperazine-1-carboxylate (745 mg, 4 mmol) inDMF (20 mL) was added N,N-diisopropylethylamine (1.43 mL, 8 mmol),followed by 3′-aminobiphenyl-4-carboxylic acid (853 mg, 4 mmol) and(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophophate(BOP, 2.12 g, 4.8 mmol). The resulting mixture was stirred at roomtemperature for 1 hour. The mixture was then poured into ice-water (40mL) with stirring. The precipitate was filtered off, washed with waterand air-dried to afford tert-butyl4-(3′-aminobiphenylcarbonyl)piperazine-1-carboxylate (1.2 g, 3.15 mmol,79% yield). The product was used for next step without furtherpurification. MS (ESI, pos. ion) m/z: 382 (M+1).

Step 2.N-(4′-(4-(1-Hydroxycyclopropanecarbonyl)piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)benzenesulfonamideor ethyl(4′-(4-(1-hydroxycyclopropane-1-carbonyl)piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)carbamate

To a solution of tert-butyl4-(3′-aminobiphenylcarbonyl)piperazine-1-carboxylate (0.2 M 1,4-dioxane,150 μL, 0.03 mmol) was added pyridine (9.7 μL, 0.12 mmol) followed bybenzenesulfonyl chloride (0.2 M in 1,4-dioxane, 300 μL, 0.06 mmol) orethyl carbonochloridate (0.2 M in 1,4-dioxane, 300 μL, 0.06 mmol). Theresulting mixture was put on a shaker at 80° C. overnight. The reactionmixture was diluted with sodium hydroxide solution (1 N in brine, 0.45mL) and ethyl acetate (0.6 mL). The organic layer was separated and theaqueous layer was extracted with ethyl acetate (0.6 mL). The combinedorganic layers were concentrated. The residue was dissolved in methanol(200 μL) and HCl solution (4 N in 1,4-dioxane, 75 μL) was added. Themixture was put on a shaker at 50° C. for 1 hour. The reaction mixturewas concentrated in vacuo and the residue was dissolved in a solution ofdimethylacetamide with 10% N,N-diisopropylethylamine (200 μL).1-Hydroxycyclopropanecarboxylic acid (0.2 M in 1,4-dioxane, 180 μL,0.036 mmol) was added followed by BOP solution (0.5 M in1,2-dichloroethane, 72 μL, 0.036 mmol). The mixture was put on a shakerat rt for 2 hours. The reaction mixture was then diluted with sodiumhydroxide solution (1 N in brine, 0.45 mL) and ethyl acetate (0.5 mL).The organic layer was separated and the aqueous layer was extracted withethyl acetate (0.6 mL). The combined organic layers were concentratedand the residue was purified by high performance liquid chromatography(Waters Autopurification MS-directed HPLC prep fraction collection withthe following conditions: Column:Waters XBridge OBD C18, 5 μm, 19×50 mm;flow rate 20 mL/min; mobile phase, water with 0.1% ammonium hydroxide(A) and methanol with 0.1% ammonium hydroxide(B) running the followinggradient 0 to 2 mins (15% B), 2 to 6 mins (15-100% B); Detector ZQ MassDetector in electrospray ionization mode) to affordN-(4′-(4-(1-hydroxycyclopropanecarbonyl)piperazine-1-carbonyl)biphenyl-3-yl)benzenesulfonamide(7.8 mg, 15 μmol, 51% yield). MS (ESI, pos. ion) m/z: 506 (M+1).

Preparation ofN-(4′-(4-(1-hydroxycyclopropanecarbonyl)piperazine-1-carbonyl)biphenyl-3-yl)oxetane-3-carboxamide

(3′-Aminobiphenyl-4-yl)(4-(1-hydroxycyclopropanecarbonyl)piperazin-1-yl)methanone(0.168 g, 0.460 mmol), N,N-diisopropylethylamine (0.241 mL, 1.379 mmol)and oxetane-3-carboxylic acid (0.055 g, 0.506 mmol) were combined in DMF(5 mL). O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.244 g, 0.644 mmol) was added to give a lightyellow solution. This was stirred for 18 h. N,N-Diisopropylethyl amine(0.120 mL, 0.687 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(0.18 g, 0.474 mmol), and oxetane-3-carboxylic acid (0.025 g, 0.244mmol) were added. Stirring was continued for 5 h. The reaction wasdiluted with 10 mL of water and stirred. Another 15 mL of water wasadded and the aqueous emulsion was extracted with 50 mL ofdichloromethane and then 20 mL of dichloromethane. The combined organiclayers were washed with 20 mL of water and then with 20 mL of brine,dried over MgSO₄ and concentrated. The material was purified via columnchromatography on silica gel (Biotage 25 g column, gradient elution with0-6% methanol/dichloromethane). The material obtained was repurified ona second silica gel column (Biotage 25 g column, 4-6.5%methanol/dichloromethane). Concentration of the fractions afforded ayellow film. This material was taken up in 40 mL of dichloromethane andwashed twice with 5 mL of dilute NaHCO₃ and once with 5 mL of brine. Thesolution was dried over MgSO₄ and concentrated to afford a yellow oil.This oil was taken up in dichloromethane and triturated with hexanes.Filtration affordedN-(4′-(4-(1-hydroxycyclopropanecarbonyl)piperazine-1-carbonyl)biphenyl-3-yl)oxetane-3-carboxamide(0.036 g, 0.076 mmol, 17%) as a yellow solid. MS (ESI, pos. ion) m/z:450 (M+1).

Step 1. 6-fluorobenzo[d]oxazole-2(3H)-thione

Into a 250-mL round-bottom flask, was placed 2-amino-5-fluorophenol (8g, 62.93 mmol, 1.00 equiv), ethoxy(potassiosulfanyl)methanethione (11.1g, 69.25 mmol, 1.10 equiv), ethanol (150 mL). The resulting solution washeated to reflux overnight in an oil bath. The reaction mixture wascooled to room temperature with a water bath and then concentrated undervacuum. The resulting slurry was diluted with 150 mL of water and its pHvalue was adjusted to 5 with acetic acid and precipitation formed. Thesolids were collected by filtration and dried in an oven. This resultedin 9.2 g (86%) of the title compound as a gray solid. LC-MS (ES, m/z)170 [M+H]⁺

Step 2. 2-chloro-6-fluorobenzo[d]oxazole

Into a 500-mL round-bottom flask, was placed6-fluoro-2,3-dihydro-1,3-benzoxazole-2-thione (9.2 g, 54.38 mmol, 1.00equiv), thionyl chloride (200 mL) and DMF (0.5 mL). The resultingsolution was stirred for 6 h at 80° C. in an oil bath. After reaction,the excess of SOCl₂ was removed under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether(0/100˜7/93). The fractions were collected and concentrated undervacuum. This resulted in 3.5 g (38%) of the title compound as brown oil.LC-MS (ES, m/z) 172 [M+H]⁺

Step 3. 4-bromo-2-fluorobenzoyl chloride

Into a 250-mL round-bottom flask, was placed 4-bromo-2-fluorobenzoicacid (10 g, 45.66 mmol), thionyl chloride (50 mL) andN,N-dimethylformamide (0.1 mL). The resulting mixture was stirred for 2h at 80° C. After cooling to room temperature, the solution concentratedunder vacuum. This resulted in 10 g (92%) of the title compound as lightyellow oil. The product was used in the next step directly withoutfurther purification.

Step 4. tert-butyl 4-(4-bromo-2-fluorobenzoyl)piperazine-1-carboxylate

Into a 250-mL round-bottom flask, was placed a solution of4-bromo-2-fluorobenzoyl chloride (10 g, 42.11 mmol, 1.00 equiv) inN,N-dimethylformamide (100 mL). This was followed by the addition oftert-butyl piperazine-1-carboxylate (7.88 g, 42.31 mmol, 1.00 equiv) inseveral portions. Then DIEA (16.25 g, 125.74 mmol, 2.99 equiv) was addedin. The resulting solution was stirred overnight at room temperature.The product was precipitated by the addition of 400 mL of H₂O. Thesolids were collected by filtration and dried in an oven. This resultedin 14 g (86%) of the title compound as a white solid. LC-MS (ES, m/z)387, 389 [M+H]⁺

Step 5. tert-butyl4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate(Intermediate 3)

Into a 2000-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of tert-butyl4-[(4-bromo-2-fluorophenyl)carbonyl]piperazine-1-carboxylate (57 g,147.19 mmol, 1.00 equiv) in N,N-dimethylformamide (800 mL),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(76.2 g, 300.07 mmol, 2.01 equiv), PdCl₂(dppf) (11 g, 15.03 mmol, 0.10equiv), KOAc (44.1 g, 449.36 mmol, 3.00 equiv). The resulting mixturewas stirred overnight at 70° C. After cooling to room temperature, themixture was poured into 3 L of H₂O. The solids were collected byfiltration, further purified by a silica gel column with ethylacetate/petroleum ether (3:7). The collected fractions were combined andconcentrated under vacuum. This resulted in 30 g (47%) of the titlecompound as a light brown solid. LC-MS (ES, m/z) 435 [M+H]⁺

Step 6. tert-butyl4-(2-fluoro-4-(6-fluorobenzo[d]oxazol-2-yl)benzoyl)piperazine-1-carboxylate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of tert-butyl4-[[2-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl]piperazine-1-carboxylate(1.26 g, 2.90 mmol, 1.00 equiv) in toluene (24 mL),2-chloro-6-fluoro-1,3-benzoxazole (500 mg, 2.91 mmol, 1.00 equiv),Pd(PPh₃)₄ (336 mg, 0.29 mmol, 0.10 equiv), sodium carbonate (12 mL, 2M),ethanol (3.3 mL). The resulting mixture was stirred overnight at 95° C.After cooling to room temperature, the resulting solution was dilutedwith 30 ml of water and extracted with 2×30 mL of ethyl acetate. Theorganic layers were combined and dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with EA/DCM (3/10). This resulted in 1.1 g (86%) of the titlecompound as a gray solid. LC-MS (ES, m/z) 444 [M+H]⁺

Step 7.(2-fluoro-4-(6-fluorobenzo[d]oxazol-2-yl)phenyl)(piperazin-1-yl)methanone

Into a 250-mL round-bottom flask, was placed a solution of tert-butyl4-[[2-fluoro-4-(6-fluoro-1,3-benzoxazol-2-yl)phenyl]carbonyl]piperazine-1-carboxylate(1.1 g, 2.48 mmol, 1.00 equiv) in dichloromethane (100 mL). To the abovehydrogen chloride gas was introduced in. The resulting solution wasstirred for 1 h at room temperature. The solids were collected byfiltration and then dissolved in water, then adjusted to pH 6˜7 withsodium bicarbonate. Then the solids were collected by filtration anddried in oven. This resulted in 700 mg (82%) of the title compound as agray solid. LC-MS (ES, m/z) 344 [M+H]⁺

Step 8.(4-(2-fluoro-4-(6-fluorobenzo[d]oxazol-2-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

Into a 50-mL round-bottom flask, was placed a solution of6-fluoro-2-[3-fluoro-4-[(piperazin-1-yl)carbonyl]phenyl]-1,3-benzoxazole(538 mg, 1.57 mmol, 1.00 equiv) in N,N-dimethylformamide (15 mL),1-hydroxycyclopropane-1-carboxylic acid (160 mg, 1.57 mmol, 1.00 equiv),HBTU (891 mg, 2.35 mmol, 1.50 equiv), DIEA (809 mg, 6.26 mmol, 4.00equiv). The resulting solution was stirred overnight at roomtemperature. The reaction mixture was then diluted with 30 mL of water.The resulting solution was extracted with 2×20 mL of dichloromethane andthe organic layers combined and dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (7:1). The fraction wascollected and concentrated. This product was re-crystallized from EA/PEin the ratio of 10/1. This resulted in 206.7 mg (30%) of the titlecompound as an off-white solid. LC-MS (ES, m/z) 428 [M+H]⁺

Step 1. tert-butyl4-(4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazine-1-carboxylate

Into a 100-mL round-bottom flask, was placed tert-butyl4-[[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl]piperazine-1-carboxylate(832 mg, 2.00 mmol, 1.00 equiv), 5-bromo-1-methyl-1H-1,3-benzodiazole(422 mg, 2.00 mmol, 1.00 equiv), Pd(PPh₃)₄ (232 mg, 0.20 mmol, 0.10equiv), sodium carbonate (2N, 5 mL), toluene (10 mL), ethanol (3 mL).The resulting mixture was stirred overnight at 95° C. in an oil bath.After cooled to room temperature, the resulting solution was dilutedwith 10 mL of water, extracted with 3×20 mL of ethyl acetate. Theorganic layers were combined, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (0/100˜100/0). The collectedfractions were combined and concentrated under vacuum. This resulted in800 mg (95%) of the title compound as a light yellow solid. LC-MS (ES,m/z): 421 [M+H]⁺

Step 2.(4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)(piperazin-1-yl)methanonehydrochloride

Into a 100-mL round-bottom flask, was placed tert-butyl4-[[4-(1-methyl-1H-1,3-benzodiazol-5-yl)phenyl]carbonyl]piperazine-1-carboxylate(800 mg, 1.90 mmol, 1.00 equiv), dichloromethane (20 mL). Then HCl gaswas introduced in. The resulting solution was stirred for 1.5 h at roomtemperature. The solids were collected by filtration and dried undervacuum. This resulted in 580 mg (95%) of the title compound as anoff-white solid. LC-MS (ES, m/z): 321 [M+H]⁺

Step 3. tert-butyl(1-(4-(4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazine-1-carbonyl)cyclopropyl)carbamate

Into a 50-mL round-bottom flask, was placed1-methyl-5-[4-[(piperazin-1-yl)carbonyl]phenyl]-1H-1,3-benzodiazolehydrochloride (580 mg, 1.63 mmol, 1.00 equiv),1-[[(tert-butoxy)carbonyl]amino]cyclopropane-1-carboxylic acid (360 mg,1.79 mmol, 1.10 equiv), HBTU (927 mg, 2.44 mmol, 1.50 equiv), DIEA (841mg, 6.51 mmol, 4.00 equiv), N,N-dimethylformamide (10 mL). The mixturewas stirred overnight at room temperature for overnight. The resultingsolution was diluted with 60 mL of water, extracted with 3×60 mL ofdichloromethane. The organic layers were combined, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with dichloromethane/methanol (80/20). Thecollected fractions were combined and concentrated under vacuum. Thisresulted in 800 mg (quantitive) of the title compound as colorless oil.LC-MS (ES, m/z): 504 [M+H]⁺

Step 4.(4-(1-aminocyclopropane-1-carbonyl)piperazin-1-yl)(4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)methanone

Into a 100-mL round-bottom flask, was placed tert-butylN-[1-[(4-[[4-(1-methyl-1H-1,3-benzodiazol-5-yl)phenyl]carbonyl]piperazin-1-yl)carbonyl]cyclopropyl]carbamate(800 mg, 1.59 mmol, 1.00 equiv), dichloromethane (50 mL). Then HCl gaswas bubbled in for 1.5 h at room temperature. The solids were collectedby filtration and washed with DCM (50 mL). Then the solids weredissolved in 5 mL of water. The pH value of the solution was adjusted to8 with potassium carbonate (2M). The resulting mixture was extractedwith 2×50 mL of dichloromethane and the organic layers combined andconcentrated under vacuum. The crude product was purified by Prep-HPLCwith the following conditions (Waters III):Column, Xbridge RP18 19*150;mobile phase, water (0.05% NH₄HCO₃) and MeCN (15% CH₃CN up to 75% in 10min); Detector, UV 220&254 nm. This resulted in 93.1 mg (15%) of thetitle compound as a white solid. LC-MS (ES, m/z) 404[M+H]⁺

Step 1. 4-Bromo-2-Fluorobenzoyl Chloride

Into a 250-mL round-bottom flask, was placed 4-bromo-2-fluorobenzoicacid (10 g, 45.66 mmol, 1.00 equiv), thionyl chloride (50 mL),N,N-dimethylformamide (0.1 mL). The resulting solution was stirred for 2h at 80° C. After cooled to room temperature, the resulting mixture wasconcentrated under vacuum. This resulted in 10 g (92%) of the titlecompound as light yellow oil. The product was used in the next stepdirectly without further purification.

Step 2. tert-butyl 4-(4-bromo-2-fluorobenzoyl)piperazine-1-carboxylate

Into a 250-mL round-bottom flask, was placed a solution of4-bromo-2-fluorobenzoyl chloride (10 g, 42.11 mmol, 1.00 equiv) inN,N-dimethylformamide (100 mL). This was followed by the addition oftert-butyl piperazine-1-carboxylate (7.88 g, 42.31 mmol, 1.00 equiv) inseveral portions. Then to this was added DIEA (16.25 g, 125.74 mmol,2.99 equiv). The resulting mixture was stirred overnight at roomtemperature. The mixture was poured into 300 mL water. The solids werecollected by filtration and dried under vacuum. This resulted in 14 g(86%) of the title compound as a white solid. LC-MS (ES, m/z): 387,389[M+H]⁺

Step 3. tert-butyl4-(4′-chloro-2′,3-difluoro-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of tert-butyl4-(4-bromo-2-fluorobenzoyl)piperazine-1-carboxylate (1 g, 2.58 mmol,1.00 equiv) in toluene (10 mL), (4-chloro-2-fluorophenyl)boronic acid(540 mg, 3.10 mmol, 1.20 equiv), Pd(PPh₃)₄ (358 mg, 0.31 mmol, 0.12equiv), sodium carbonate (2 M in water, 5 mL), ethanol (1.4 mL). Theresulting mixture was stirred overnight at 105° C. After cooled to roomtemperature, the resulting solution was diluted with 20 mL of H₂O andextracted with 3×20 mL of ethyl acetate. The organic layers werecombined, washed with 3×20 mL of brine, dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (3:7). Thecollected fractions were combined and concentrated under vacuum. Thisresulted in 1 g (89%) of the title compound as a light yellow solid.LC-MS (ES, m/z): 437[M+H]⁺

Step 4.(4′-chloro-2′,3-difluoro-[1,1′-biphenyl]-4-yl)(piperazin-1-yl)methanonehydrochloride

Into a 100-mL round-bottom flask, was placed tert-butyl4-(4′-chloro-2′,3-difluoro-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate(1 g, 2.28 mmol, 1.00 equiv), hydrochloric acid in 1,4-dioxane (4 M, 30mL). The resulting solution was stirred for 30 min at room temperature.The resulting mixture was concentrated under vacuum. This resulted in600 mg (78%) of the title compound as an off-white solid. LC-MS (ES,m/z): 337[M+H]⁺

Step 5.(4-(4′-chloro-2′,3-difluoro-[1,1′-biphenyl]-4-carbonyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

Into a 100-mL round-bottom flask, was placed a solution of(4′-chloro-2′,3-difluoro-[1,1′-biphenyl]-4-yl)(piperazin-1-yl)methanonehydrochloride (500 mg, 1.48 mmol, 1.00 equiv), N,N-dimethylformamide (20mL), 1-hydroxycyclopropane-1-carboxylic acid (166 mg, 1.63 mmol, 1.10equiv), HBTU (841 mg, 2.22 mmol, 1.49 equiv), DIEA (764 mg, 5.91 mmol,3.98 equiv). The resulting solution was stirred overnight at roomtemperature. The mixture was poured into 80 mL of water andprecipitation was formed. The solids were collected by filtration andapplied onto a silica gel column with ethyl acetate/hexane (3:2). Thecollected fractions were combined and concentrated under vacuum. Thisresulted in 260 mg (42%) of the title compound as an off-white solid.LC-MS (ES, m/z): 421[M+H]⁺

Step 1. 5-bromo-N-methyl-2H-benzo[d][1,2,3]triazole

Into a 100-mL round-bottom flask, was placed a solution of6-bromo-1H-1,2,3-benzotriazole (600 mg, 3.03 mmol, 1.00 equiv) inN,N-dimethylformamide (10 mL). This was followed by the addition ofsodium hydride (60% in oil, 303 mg, 7.58 mmol, 2.50 equiv) in portionsat 0° C. After stirring for 30 min at 0° C., CH₃I (650 mg, 4.58 mmol,1.50 equiv) was added in drop wise. The resulting solution was allowedto react, with stirring, for an additional 18 h at 20° C. The reactionmixture was then diluted with 10 mL of ice/water, extracted with 3×20 mLof ethyl acetate. The organic layers were combined, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with PE:EA (200:1˜3:1). This resulted in 700 mg(crude) of a mixture of the title compounds as a yellow oil. LC-MS (ES,m/z): 212, 214 [M+H]⁺

Step 2. tert-butyl4-(4-(N-methyl-2H-benzo[d][1,2,3]triazol-5-yl)benzoyl)piperazine-1-carboxylate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tert-butyl4-[[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl]piperazine-1-carboxylate(1.51 g, 3.63 mmol, 1.10 equiv), the mixture of5-bromo-N-methyl-2H-benzo[d][1,2,3]triazoles (700 mg, 3.30 mmol, 1.00equiv), Pd(PPh₃)₄ (382 mg, 0.33 mmol, 0.10 equiv) and toluene/EtOH(30/4.5 mL), sodium carbonate (15 mL, 2M). The resulting mixture wasstirred for 18 h at 90° C. After cooled to room temperature, thereaction mixture was diluted with 50 mL of water, extracted with 3×30 mLof ethyl acetate. The organic layers were combined, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with dichloromethane/methanol (200/1˜20/1).This resulted in 1.2 g (crude) of a mixture of the title compounds as alight yellow solid. LC-MS (ES, m/z): 422 [M+H]⁺

Step 3.(4-(N-methyl-2H-benzo[d][1,2,3]triazol-5-yl)phenyl)(piperazin-1-yl)methanonehydrochloride

Into a 100-mL round-bottom flask, was placed the mixture of tert-butyl4-(4-(N-methyl-2H-benzo[d][1,2,3]triazol-5-yl)benzoyl)piperazine-1-carboxylate(1.2 g, 2.85 mmol, 1.00 equiv) and dichloromethane (50 mL). Thenhydrogen chloride (gas) was introduced in. The resulting solution wasstirred for 30 min at 20° C. The resulting solids were collected byfiltration and dried under reduced pressure. This resulted in 800 mg(79%) of a mixture of the title compounds as a light yellow solid. LC-MS(ES, m/z): 322 [M+H]⁺

Step 4.(4-(1-hydroxycyclopropane-1-carbonyl)piperazin-1-yl)(4-(2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)phenyl)methanone

Into a 100-mL round-bottom flask, was placed a solution of1-hydroxycyclopropane-1-carboxylic acid (240 mg, 2.35 mmol, 1.10 equiv)in N,N-dimethylformamide (10 mL), the mixture of(4-(N-methyl-2H-benzo[d][1,2,3]triazol-5-yl)phenyl)(piperazin-1-yl)methanonehydrochloride (766 mg, 2.14 mmol, 1.00 equiv, 98%), HBTU (1.22 g, 3.22mmol, 1.50 equiv), DIEA (1.11 g, 8.59 mmol, 4.00 equiv). The resultingsolution was stirred for 18 h at 20° C. The reaction mixture was dilutedwith 20 mL of water, extracted with 3×20 mL of ethyl acetate. Theorganic layers were combined, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by Prep-HPLC withthe following conditions (Waters III):Column, XBridge Prep Cis OBDColumn, 5 um, 19*150 mm; mobile phase, water with 0.03% NH₃H₂O and MeCN(16% MeCN up to 34% in 8 min); Detector, 254&220 nm. This resulted in 90mg (10%) of the title compound as a light yellow solid. LC-MS (ES, m/z)406[M+H]⁺

Step 1. (4-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)phenyl)boronicacid

Into a 1 L round-bottom flask was placed Intermediate 3 (12.5 g, 30.03mmol, 1.00 eqiv) a solution of sodium periodate (32.1 g, 150.00 mmol,5.00 eqiv) in acetone (300 mL), ammonium acetate (150 mL, 5.00 eqiv,1M). The resulting solution was stirred for 18 h at RT. The resultingsolution was diluted with 300 mL of water and extracted with 3×100 mL ofethyl acetate. The organic layers were combined and dried over sodiumsulfate. The solids were filtered out and the solution was concentratedin vacuo. This afforded the title compound (10.1 g, 96%) as a lightyellow solid. LC-MS (ES, m/z) 335[M+H]⁺

Step 2. tert-butyl4-(4-(2-methyl-1H-benzo[d]imidazol-1-yl)benzoyl)piperazine-1-carboxylate

Into a 250-mL round-bottom flask, was placed a solution of(4-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)phenyl)boronic acid(3.34 g, 9.05 mmol, 2.00 equiv) in dichloromethane (50 mL),2-methyl-1H-benzo[d]imidazole (660 mg, 4.99 mmol, 1.00 equiv), Cu(OAc)₂(1.23 mg, 1.50 equiv), pyridine (790 mg, 9.99 mmol, 2.00 equiv), 4 Åmolecular sieves (3 g). The resulting mixture was stirred for 18 h at20° C. The solids were filtered out. The filtrate was concentrated undervacuum. The residue was applied onto a silica gel column with DCM/MeOH(200/1˜20/1). This resulted in 1 g (27%) of the title compound as yellowoil. LC-MS (ES, m/z): 421[M+H]⁺

Step 3.(4-(2-methyl-1H-benzo[d]imidazol-1-yl)phenyl)(piperazin-1-yl)methanonehydrochloride

Into a 100-mL round-bottom flask, was placed tert-butyl4-(4-(2-methyl-1H-benzo[d]imidazol-1-yl)benzoyl)piperazine-1-carboxylate(960 mg, 2.28 mmol, 1.00 equiv), DCM (30 mL), THF (30 mL). Then hydrogenchloride (gas) was introduced in. The resulting solution was stirred for30 min at 20° C. The solids were collected by filtration and dried undervacuum. This resulted in 600 mg of the title compound as a light yellowsolid. LC-MS (ES, m/z): 321[M+H]⁺

Step 4.(4-(1-hydroxycyclopropane-1-carbonyl)piperazin-1-yl)(4-(2-methyl-1H-benzo[d]imidazol-1-yl)phenyl)methanone

Into a 100-mL round-bottom flask, was placed1-hydroxycyclopropane-1-carboxylic acid (190 mg, 1.86 mmol, 1.10 equiv),(4-(2-methyl-1H-benzo[d]imidazol-1-yl)phenyl)(piperazin-1-yl)methanonehydrochloride (600 mg, 1.68 mmol, 1.00 equiv), HBTU (955 mg, 2.52 mmol,1.50 equiv), N,N-dimethylformamide (10 mL), DIEA (867 mg, 6.71 mmol,4.00 equiv). The resulting solution was stirred for 18 h at 20° C. Thereaction mixture was diluted with 20 mL of water, extracted with 3×20 mLof ethyl acetate. All the organic layers were combined, dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by Prep-HPLC with the following conditions (Waters I):Column,Xbridge Prep C18 OBD column, 5 um, 19*150 mm; mobile phase, Water (0.05%NH₄HCO₃) and CH₃CN (16% CH₃CN up to 34% in 10 min); Detector, UV 220&254nm. This resulted in 130 mg (19%) of the title compound as a whitesolid. LC-MS (ES, m/z): 405[M+H]⁺

Step 1. tert-butyl4-(4-(2-methyl-1H-indol-1-yl)benzoyl)piperazine-1-carboxylate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of tert-butyl4-[(4-bromophenyl)carbonyl]piperazine-1-carboxylate (Intermediate 1(X=H), 1.69 g, 4.58 mmol, 1.00 equiv) in toluene (50 mL),2-methyl-1H-indole (600 mg, 4.57 mmol, 1.00 equiv), CuI (87 mg, 0.46mmol, 0.10 equiv), potassium carbonate (1.9 g, 13.75 mmol, 3.00 equiv),(1R,2R)-1-N, 2-N-dimethylcyclohexane-1,2-diamine (130 mg, 0.91 mmol,0.20 equiv). The resulting mixture was stirred overnight at 120° C.After cooled to room temperature, the reaction mixture was diluted with50 mL of H₂O, extracted with 3×50 mL of ethyl acetate. The organiclayers were combined, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:1). The collected fractionswere combined and concentrated under vacuum. This resulted in 1.4 g(73%) of the title compound as a red solid. LC-MS (ES, m/z): 420[M+H]⁺

Step 2. (4-(2-methyl-1H-indol-1-yl)phenyl)(piperazin-1-yl)methanonehydrochloride (Intermediate 4)

Into a 100-mL round-bottom flask, was placed a solution of tert-butyl4-(4-(2-methyl-1H-indol-1-yl)benzoyl)piperazine-1-carboxylate (1.4 g,3.34 mmol) in dichloromethane (30 mL). To the above HCl gas wasintroduced in. The resulting solution was stirred for 30 min at roomtemperature. The resulting mixture was concentrated under vacuum. Thisresulted in 1.4 g (59%) of the title compound as a red solid. LC-MS (ES,m/z): 320[M+H]⁺

Step 3.(4-(1-hydroxycyclopropane-1-carbonyl)piperazin-1-yl)(4-(2-methyl-1H-indol-1-yl)phenyl)methanone

Into a 100-mL round-bottom flask, was placed a solution of(4-(2-methyl-1H-indol-1-yl)phenyl)(piperazin-1-yl)methanonehydrochloride (658 mg, 1.85 mmol, 1.00 equiv) in N,N-dimethylformamide(20 mL), 1-hydroxycyclopropane-1-carboxylic acid (189 mg, 1.85 mmol,1.00 equiv), HBTU (1.05 g, 2.77 mmol, 1.50 equiv), DIEA (955 mg, 7.39mmol, 4.00 equiv). The resulting solution was stirred overnight at roomtemperature. The reaction mixture was diluted with 30 mL of water andextracted with 3×30 mL of ethyl acetate. The organic layers werecombined, dried over sodium sulfate anhydrous and concentrated undervacuum. The residue was applied onto a silica gel column withdichloromethane/methanol (10:1). The collected fractions were combinedand concentrated under vacuum. This resulted in 112.3 mg (15%) of thetitle compound as a light brown solid. LC-MS (ES, m/z): 404[M+H]⁺

Step 1. tert-butyl 4-(4-(indolin-1-yl)benzoyl)piperazine-1-carboxylate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed 2,3-dihydro-1H-indole (390 mg, 3.27mmol, 1.00 equiv), tert-butyl4-[(4-bromophenyl)carbonyl]piperazine-1-carboxylate (Intermediate 1(R=H), 1.5 g, 3.60 mmol, 1.10 equiv), Cs₂CO₃ (3.74 g, 11.48 mmol, 3.51equiv), toluene (50 mL), RuPhos palladium(II) biphenyl-2-amine mesylate(276 mg). The resulting mixture was stirred overnight at 85° C. Aftercooled to room temperature, the resulting mixture was concentrated undervacuum and re-dissolved with 200 mL of EA. The resulting mixture waswashed with 3×50 mL of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (50:50). This resulted in 1 g(75%) of the title compound as a yellow solid. LC-MS (ES, m/z):408[M+H]⁺

Step 2. (4-(indolin-1-yl)phenyl)(piperazin-1-yl)methanone hydrochloride

Into a 100-mL round-bottom flask, was placed tert-butyl4-(4-(indolin-1-yl)benzoyl)piperazine-1-carboxylate (1 g, 2.45 mmol,1.00 equiv), a solution of hydrogen chloride in 1,4-dioxane (4M, 20 mL).The resulting solution was stirred for 1 h at room temperature. Thesolids were collected by filtration and dried under vacuum. Thisresulted in 800 mg (95%) of the title compound as a yellow solid. LC-MS(ES, m/z): 308[M+H]⁺

Step 3.(4-(1-hydroxycyclopropane-1-carbonyl)piperazin-1-yl)(4-(indolin-1-yl)phenyl)methanone

Into a 100-mL round-bottom flask, was placed(4-(indolin-1-yl)phenyl)(piperazin-1-yl)methanone hydrochloride (540 mg,1.57 mmol, 1.00 equiv), 1-hydroxycyclopropane-1-carboxylic acid (160 mg,1.57 mmol, 1.00 equiv), N,N-dimethylformamide (20 mL), HBTU (892 mg,2.35 mmol, 1.50 equiv), DIEA (810 mg, 6.27 mmol, 3.99 equiv). Theresulting solution was stirred overnight at room temperature. Thereaction mixture was diluted with 50 mL of EA, washed with 3×30 mL ofbrine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by Prep-HPLC with the followingconditions (Waters I):Column, SunFire Prep C18, 5 um, 19*100 mm; mobilephase, Water (0.05% NH₄HCO₃) and CH₃CN (50% CH₃CN up to 100% in 10 min);Detector, UV 220&254 nm. This resulted in 63.8 mg (10%) of the titlecompound as an off-white solid. LC-MS (ES, m/z): 392[M+H]⁺

Step 1. tert-butyl4-(4-(3,4-dihydroquinolin-1(2H)-yl)benzoyl)piperazine-1-carboxylate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed Pd₂(dba)₄ (305 mg), DavePhos (627mg), toluene (50 mL). The mixture was stirred at room temperature for 30min. Then 1,2,3,4-tetrahydroquinoline (700 mg, 5.26 mmol, 1.00 equiv),tert-butyl 4-[(4-bromophenyl)carbonyl]piperazine-1-carboxylate(Intermediate 1, 1.94 g, 5.25 mmol, 1.00 equiv), t-BuOK (1.18 g, 10.52mmol, 2.00 equiv) were added in. The system was evacuated andback-filled with N₂ for 5 times. The resulting mixture was stirred for18 h at 120° C. in an oil bath. After cooled to room temperature, theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether(0/100˜45/55). The collected fractions were combined and concentratedunder vacuum. This resulted in 540 mg (24%) of the title compound as ayellow solid. LC-MS (ES, m/z): 422 [M+H]⁺

Step 2.(4-(3,4-dihydroquinolin-1(2H)-yl)phenyl)(piperazin-1-yl)methanonehydrochloride

Into a 100-mL round-bottom flask, was placed tert-butyl4-(4-(3,4-dihydroquinolin-1(2H)-yl)benzoyl)piperazine-1-carboxylate (540mg, 1.28 mmol, 1.00 equiv), dichloromethane (40 mL). Then hydrogenchloride gas was bubbled in. The resulting solution was stirred for 2 hat room temperature. The resulting mixture was concentrated undervacuum. This resulted in 635 mg (quantitive) of the title compound as ayellow solid. LC-MS (ES, m/z): 322 [M+H]⁺

Step 3.(4-(4-(3,4-dihydroquinolin-1(2H)-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

Into a 100-mL round-bottom flask, was placed1-hydroxycyclopropane-1-carboxylic acid (635 mg, 6.22 mmol, 1.00 equiv),(4-(3,4-dihydroquinolin-1(2H)-yl)phenyl)(piperazin-1-yl)methanonehydrochloride (181 mg, 0.51 mmol, 0.08 equiv), HBTU (1.34 g, 3.53 mmol,0.57 equiv), N,N-dimethylformamide (15 mL), DIEA (457 mg, 3.54 mmol,0.57 equiv). The resulting solution was stirred overnight at roomtemperature. The reaction mixture was diluted with 60 mL of EA, washedwith 4×20 mL of water and 1×20 mL of brine. The organic phase was driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(0/100˜100/0). The resulting crude product was further purified byPrep-HPLC with the following conditions (Waters III):Column, XbridgeRP18 19*150; mobile phase, water (0.05% NH₄HCO₃) and MeCN (15% CH₃CN upto 75% in 10 min); Detector, UV 220&254 nm. This resulted in 66.3 mg(3%) of the title compound as a purple solid. LC-MS (ES, m/z): 406[M+H]⁺

Step 1. tert-butyl4-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-benzo[d]imidazol-5and 6-yl)benzoyl)piperazine-1-carboxylate

Into a 250-mL round-bottom flask, was placed tert-butyl4-(4-(1H-benzo[d]imidazol-5-yl)benzoyl)piperazine-1-carboxylate (1 g,2.46 mmol, 1.00 equiv), (2-bromoethoxy)(tert-butyl)dimethylsilane (883mg, 3.69 mmol, 1.50 equiv), N,N-dimethylformamide (50 mL), Cs₂CO₃ (2.41g, 7.40 mmol, 3.01 equiv). The resulting mixture was stirred overnightat 70° C. After cooled to room temperature, the reaction mixture wasdiluted with 100 mL of EA, washed with 3×50 mL of water and 50 mL ofbrine. The organic phase was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by Prep-HPLC withthe following conditions (Waters I):Column, SunFire Prep C18, 5 um,19*100 mm; mobile phase, Water (0.05% NH₄HCO₃) and CH₃CN (55% CH₃CN upto 75% in 7 min); Detector, UV 220&254 nm. This resulted in 380 mg (27%)of tert-butyl4-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-benzo[d]imidazol-5-yl)benzoyl)piperazine-1-carboxylateas a yellow solid and 390 mg (28%) tert-butyl4-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-benzo[d]imidazol-6-yl)benzoyl)piperazine-1-carboxylateas a yellow solid. LC-MS (ES, m/z): 565[M+H]⁺

Step 2.(4-(1-(2-hydroxyethyl)-1H-benzo[d]imidazol-6-yl)phenyl)(piperazin-1-yl)methanonehydrochloride

Into a 100-mL round-bottom flask, was placed tert-butyl4-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-benzo[d]imidazol-6-yl)benzoyl)piperazine-1-carboxylate(380 mg, 0.67 mmol, 1.00 equiv) and dioxane (40 mL). Then HCl gas wasintroduced in. The resulting solution was stirred for 1 h at roomtemperature. The resulting mixture was concentrated under vacuum. Thisresulted in 250 mg (96%) of the title compound as a yellow solid. LC-MS(ES, m/z): 351[M+H]⁺

Step 3.(4-(1-hydroxycyclopropane-1-carbonyl)piperazin-1-yl)(4-(1-(2-hydroxyethyl)-1H-benzo[d]imidazol-5-yl)phenyl)methanone

Into a 100-mL round-bottom flask, was placed(4-(1-(2-hydroxyethyl)-1H-benzo[d]imidazol-6-yl)phenyl)(piperazin-1-yl)methanonehydrochloride (250 mg, 0.65 mmol, 1.00 equiv),1-hydroxycyclopropane-1-carboxylic acid (66 mg, 0.65 mmol, 1.00 equiv),N,N-dimethylformamide (20 mL), HBTU (367 mg, 0.97 mmol, 1.50 equiv),DIEA (333 mg, 2.58 mmol, 3.99 equiv). The resulting solution was stirredovernight at room temperature. The reaction mixture was washed withwater, dried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by Prep-HPLC with the following conditions (Waters I):Column,SunFire Prep C18, 5 um, 19*100 mm; mobile phase, Water (0.05% NH₄HCO₃)and CH₃CN (55% CH₃CN up to 75% in 7 min); Detector, UV 220&254 nm. Thisresulted in 75 mg (27%) of the title compound as an off-white solid.LC-MS (ES, m/z): 435[M+H]⁺

Step 1. tert-butyl (3-(3-bromophenyl)isoxazol-5-yl)carbamate

Into a 250-mL round-bottom flask, was placed a solution of3-(3-bromophenyl)-1,2-oxazol-5-amine (1 g, 4.18 mmol, 1.00 equiv) indichloromethane (40 mL), Boc₂O (1.83 g, 8.38 mmol, 2.00 equiv),triethylamine (1.27 g, 12.55 mmol, 3.00 equiv), 4-dimethylaminopyridine(51.24 mg, 0.42 mmol, 0.10 equiv). The resulting solution was stirredfor 1 h at room temperature. The resulting mixture was washed with 2×20mL of hydrochloric acid (0.5M), dried over anhydrous sodium sulfate,concentrated under vacuum. This resulted in 1.42 g (crude) of the titlecompound as an off-white solid. LC-MS (ES, m/z): 339[M+H]⁺

Step 2. benzyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate(Intermediate 5)

Into a 1 L round-bottom flask was placed benzyl piperazine-1-carboxylate(15 g, 68.10 mmol, 1.00 equiv),4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (16.9 g, 68.12 mmol,1.00 equiv), EDC (14.4 g, 75.12 mmol, 1.10 equiv), HOBt (5.8 g, 42.92mmol, 0.50 equiv), and triethylamine (27.6 g 272.75 mmol, 4.00 equiv) indichloromethane (300 mL). The resulting solution was stirred for 18 h atRT. The mixture was then washed with 0.5M sodium carbonate (aq, 75 mL).The resulting mixture was then washed with 0.5M HCl (aq, 75 mL) followedby 0.5M sodium carbonate (aq, 75 mL). The solution was concentrated invacuo and the crude product was recrystallized from tBME/hexane (1:1).This afforded the title compound (26 g, 84%) as a white solid. LC-MS(ES, m/z): 451 [M+H]⁺

Step 3. benzyl4-(3′-(5-((tert-butoxycarbonyl)amino)isoxazol-3-yl)-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of tert-butyl(3-(3-bromophenyl)isoxazol-5-yl)carbamate (1.42 g, 4.19 mmol, 1.00equiv) in 1,4-dioxane (30 mL), benzyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate(1.89 g, 4.20 mmol, 1.00 equiv), Pd(dppf)Cl₂—CH₂Cl₂ (410 mg, 0.50 mmol,0.12 equiv), Cs₂CO₃ (4.11 g, 12.61 mmol, 3.01 equiv), water (10 mL). Theresulting solution was stirred overnight at 60° C. After cooled to roomtemperature, the reaction mixture was diluted with 30 mL of H₂O,extracted with 3×30 mL of ethyl acetate. The organic layers werecombined, washed with 30 mL of brine, dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:1). Thecollected fractions were combined and concentrated under vacuum. Thisresulted in 780 mg (32%) of the title compound as an off-white solid.LC-MS (ES, m/z): 583 [M+H]⁺

Step 4. tert-butyl(3-(4′-(piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)isoxazol-5-yl)carbamate

Into a 100-mL round-bottom flask, was placed benzyl4-(3′-(5-((tert-butoxycarbonyl)amino)isoxazol-3-yl)-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate(1.8 g, 3.09 mmol, 1.00 equiv), methanol (40 mL) and Lindlar catalyst(1.8 g). The flask was evacuated and back-filled with hydrogen for 6times. The resulting solution was stirred overnight at room temperature.The solids were filtered out. The filtrate was concentrated undervacuum. The residue was applied onto a silica gel column withdichloromethane/methanol (90:10). The collected fractions were combinedand concentrated under vacuum. This resulted in 850 mg (61%) of thetitle compound as a light yellow solid. LC-MS (ES, m/z): 449[M+H]⁺

Step 5. tert-butyl(3-(4′-(4-(1-hydroxycyclopropane-1-carbonyl)piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)isoxazol-5-yl)carbamate

Into a 100-mL round-bottom flask, was placed a solution of tert-butyl(3-(4′-(piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)isoxazol-5-yl)carbamate(850 mg, 1.90 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL),1-hydroxycyclopropane-1-carboxylic acid (194 mg, 1.90 mmol, 1.00 equiv),HBTU (1.08 g, 2.85 mmol, 1.50 equiv), DIEA (980 mg, 7.58 mmol, 4.00equiv). The resulting solution was stirred overnight at roomtemperature. The reaction mixture was diluted with 30 mL of EA, washedwith 3×30 mL of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with dichloromethane/methanol (90:10). The collected fractionswere combined and concentrated under vacuum. This resulted in 600 mg(59%) of the title compound as a brown solid. LC-MS (ES, m/z): 533[M+H]⁺

Step 6.(4-(3′-(5-aminoisoxazol-3-yl)-[1,1′-biphenyl]-4-carbonyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

Into a 100-mL round-bottom flask, was placed tert-butyl(3-(4′-(4-(1-hydroxycyclopropane-1-carbonyl)piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)isoxazol-5-yl)carbamate(600 mg, 1.13 mmol, 1.00 equiv), dichloromethane (30 mL). To the aboveHCl gas was introduced in. The resulting solution was stirred for 1 h atroom temperature. The mixture was concentrated and dissolved in 5 mLmethanol. The pH value of the solution was adjusted to 8 with saturatedsodium bicarbonate solution. The resulting solution was extracted with2×30 mL of dichloromethane. The organic layers were combined, dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by Prep-HPLC with the following conditions (Waters I):Column,Xbridge Prep C18 OBD column, 5 um, 19*150 mm; mobile phase, Water (0.05%NH₄HCO₃) and CH₃CN (30% CH₃CN up to 70% in 9 min); Detector, UV 220&254nm. This resulted in 107.4 mg (22%) of the title compound as a whitesolid. LC-MS (ES, m/z): 433 [M+H]⁺

Step 1. 4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoic acid

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (2.35 g, 9.47 mmol,1.00 equiv) in CH₃CN/toluene (70/12 mL),5-bromo-1-methyl-1H-benzo[d]imidazole (2 g, 9.48 mmol, 1.00 equiv),Pd(PPh₃)₄ (548 mg, 0.47 mmol, 0.05 equiv), sodium carbonate (0.4M, 50mL, 2.00 equiv). The resulting solution was stirred for 18 h at 90° C.After cooled to room temperature, the reaction mixture was poured into50 ml of water. The mixture was washed with 2×100 mL of ethyl acetateand the aqueous layer was collected. The pH value of the solution wasadjusted to 4 with hydrochloric acid (1N). The solids were collected byfiltration and dried under vacuum. This resulted in 2 g (84%) of thetitle compound as a white solid, which was dried under vacuum. LC-MS(ES, m/z): 253 [M+H]⁺

Step 2. tert-butyl(R)-2-methyl-4-(4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazine-1-carboxylate

Into a 50-mL round-bottom flask, was placed a solution of4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoic acid (600 mg, 2.38 mmol,1.00 equiv) in N,N-dimethylformamide (15 mL), tert-butyl(2R)-2-methylpiperazine-1-carboxylate (476 mg, 2.38 mmol, 1.00 equiv),HBTU (1.35 g, 3.56 mmol, 1.50 equiv), DIEA (1.22 g, 9.44 mmol, 4.00equiv). The resulting solution was stirred overnight at roomtemperature. The reaction mixture was poured into 100 mL of water,extracted with 3×100 mL of dichloromethane. The organic layers werecombined, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1/15). This resulted in 650 mg (63%) of thetitle compound as red oil. LC-MS (ES, m/z): 435 [M+H]⁺

Step 3.(R)-(4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)(3-methylpiperazin-1-yl)methanonehydrochloride

Into a 50-mL round-bottom flask, was placed a solution of tert-butyl(R)-2-methyl-4-(4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazine-1-carboxylate (650 mg, 1.50mmol, 1.00 equiv) in dichloromethane (20 mL). To the above hydrogenchloride (gas) was introduced in. The resulting solution was stirred for0.5 h at room temperature. The resulting mixture was concentrated undervacuum. The residue was triturated with 2×100 mL of ether. The solidswere collected by filtration and dried under vacuum. This resulted in500 mg (90%) of the title compound as a red solid. LC-MS (ES, m/z): 335[M+H]⁺

Step 4.(R)-(4-(1-hydroxycyclopropane-1-carbonyl)-3-methylpiperazin-1-yl)(4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)methanone

Into a 50-mL round-bottom flask, was placed a solution of(R)-(4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)(3-methylpiperazin-1-yl)methanonehydrochloride (500 mg, 1.35 mmol, 1.00 equiv) in N,N-dimethylformamide(15 mL), 1-hydroxycyclopropane-1-carboxylic acid (137 mg, 1.34 mmol,1.00 equiv), HBTU (766 mg, 2.02 mmol, 1.50 equiv), DIEA (695 mg, 5.38mmol, 4.00 equiv). The resulting solution was stirred for overnight atroom temperature. The reaction mixture was poured into 100 mL of water,extracted with 3×50 mL of dichloromethane. The organic layers werecombined, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by Prep-HPLC with the followingconditions (IntelFlash-1):Column , C₁₈ silica gel; mobile phase,CH₃CN/water with 0.05% NH₄HCO₃=20% increasing to CH₃CN/water with 0.05%NH₄HCO₃=60% within 30 min; Detector, UV 254&220 nm. This resulted in200.3 mg (36%) of the title compound as a white solid. LC-MS (ES, m/z):419 [M+H]⁺

Step 1. 7-benzyl 4-(tert-butyl)4,7-diazaspiro[2.5]octane-4,7-dicarboxylate

Into a 100-mL round-bottom flask, was placed a solution of tert-butyl4,7-diazaspiro[2.5]octane-4-carboxylate (3 g, 14.13 mmol, 1.00 equiv)and TEA (4.25 g, 42.00 mmol, 2.97 equiv) in dichloromethane (30 mL).This was followed by the addition of CbzCl (2.88 g, 16.88 mmol, 1.19equiv) dropwise with stirring at 0° C. The resulting solution wasstirred for 3 h at 25° C. The reaction mixture was diluted with 50 mL ofwater, extracted with 3×50 mL of dichloromethane. The organic layerswere combined, washed with 2×100 mL of sodium carbonate solution (2M),dried over Na₂SO₄, and concentrated under vacuum. This resulted in 4 g(82%) of the title compound as yellow oil. LC-MS (ES, m/z) 347 [M+H]⁺

Step 2. benzyl 4,7-diazaspiro[2.5]octane-7-carboxylate hydrochloride

Into a 100-mL round-bottom flask, was placed a solution of 7-benzyl4-tert-butyl 4,7-diazaspiro[2.5]octane-4,7-dicarboxylate (4 g, 11.55mmol, 1.00 equiv) in dichloromethane/tetrahydrofuran (20/20 mL). To theabove solution, hydrogen chloride (gas) was introduced in. The resultingsolution was stirred for 3 h at 25° C. The solids were collected byfiltration. This resulted in 3 g (crude) of the title compound as ayellow oil. LC-MS (ES, m/z) 247 [M+H]⁺

Step 3. benzyl4-(4-(6-fluorobenzo[d]oxazol-2-yl)benzoyl)-4,7-diazaspiro[2.5]octane-7-carboxylate

Into a 100-mL round-bottom flask, was placed HATU (1.55 g, 4.08 mmol,1.00 equiv), 4-(6-fluoro-1,3-benzoxazol-2-yl)benzoic acid (951 mg, 3.70mmol, 0.91 equiv), benzyl 4,7-diazaspiro[2.5]octane-7-carboxylatehydrogen chloride salt (1 g, 4.06 mmol, 1.00 equiv), DIEA (955 mg, 7.39mmol, 1.82 equiv) and N,N-dimethylformamide (30 mL). The resultingsolution was stirred for 18 h at 25° C. The mixture was then dilutedwith 50 mL of EA, washed with 2×50 mL of water, dried over Na₂SO₄ andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (10%-90%). This resulted in1.2 g (crude) of the title compound as yellow oil. LC-MS (ES, m/z): 486[M+H]⁺

Step 4.(4-(6-fluorobenzo[d]oxazol-2-yl)phenyl)(4,7-diazaspiro[2.5]octan-4-yl)methanone

Into a 100-mL round-bottom flask, was placed benzyl4-[[4-(6-fluoro-1,3-benzoxazol-2-yl)phenyl]carbonyl]-4,7-diazaspiro[2.5]octane-7-carboxylate(Intermediate 2, 1.2 g, 2.47 mmol, 1.00 equiv), palladium on activecarbon (1.2 g) and methanol (30 mL). Then the flask was evacuated andback-filled with hydrogen for three times. The resulting solution wasstirred for 3 h at 25° C. The solids were filtered out. The filtrate wasconcentrated under vacuum. This resulted in 700 mg (crude) of the titlecompound as a light yellow solid. LC-MS (ES, m/z): 352 [M+H]⁺

Step 5.(4-(4-(6-fluorobenzo[d]oxazol-2-yl)benzoyl)-4,7-diazaspiro[2.5]octan-7-yl)(1-hydroxycyclopropyl)methanone

Into a 100-mL round-bottom flask, was placed HATU (658 mg, 1.73 mmol,1.00 equiv), 1-hydroxycyclopropane-1-carboxylic acid (160 mg, 1.57 mmol,0.91 equiv),2-[4-([4,7-diazaspiro[2.5]octan-4-yl]carbonyl)phenyl]-6-fluoro-1,3-benzoxazole(608 mg, 1.73 mmol, 1.00 equiv), DIEA (406 mg, 3.14 mmol, 1.82 equiv)and N,N-dimethylformamide (15 mL). The resulting solution was stirredfor 18 h at 25° C. The resulting mixture was concentrated under vacuum.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (10%-90%). The crude product was purified byPrep-HPLC with the following conditions (Waters I):Column, Xbridge PrepC18 OBD column, 5 um, 19*150 mm; mobile phase, Water (0.05% NH₄HCO₃) andCH₃CN (10% CH₃CN up to 40% in 9 min); Detector, UV 220&254 nm. Thisresulted in 171.6 mg (23%) of the title compound as a white solid. LC-MS(ES, m/z): 436 [M+H]⁺

Step 1. benzyl4-(3′-(5-((tert-butoxycarbonyl)amino)-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of benzyl4-[[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl]piperazine-1-carboxylate(Intermediate 5, 710 mg, 1.58 mmol, 1.00 equiv) in 1,4-dioxane (20 mL),tert-butyl N-[3-(3-bromophenyl)-1H-pyrazol-5-yl]carbamate (533.2 mg,1.58 mmol, 1.00 equiv), Pd(dppf)Cl₂ (115.5 mg, 0.16 mmol, 0.10 equiv),sodium carbonate (2M, 5 mL). The resulting mixture was stirred overnightat 85° C. After cooled to room temperature, the reaction mixture wasdiluted with 30 mL of water, extracted with 2×100 mL of ethyl acetate.The organic layers were combined, dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (4/1). This resulted in 300 mg(33%) of the title compound as a yellow solid. LC-MS (ES, m/z):582[M+H]⁺

Step 2. tert-butyl(3-(4′-(piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazol-5-yl)carbamate

Into a 50-mL round-bottom flask, was placed a solution of benzyl4-(3′-(5-((tert-butoxycarbonyl)amino)-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate(670 mg, 1.15 mmol, 1.00 equiv) in methanol (20 mL). This was followedby the addition of Palladium carbon (670 mg). To the above hydrogen wasintroduced in. The resulting solution was stirred for 5 h at roomtemperature. The solids were filtered out. The filtrate was concentratedunder vacuum. This resulted in 515.7 mg (100%) of the title compound asan orange solid. LC-MS (ES, m/z): 448[M+H]⁺

Step 3. tert-butyl(3-(4′-(4-(1-hydroxycyclopropane-1-carbonyl)piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazol-5-yl)carbamate

Into a 250-mL round-bottom flask, was placed a solution of tert-butyl(3-(4′-(piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazol-5-yl)carbamate(515.7 mg, 1.15 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL),1-hydroxycyclopropane-1-carboxylic acid (117 mg, 1.15 mmol, 1.00 equiv),HBTU (654 mg, 1.72 mmol, 1.50 equiv), DIEA (445.5 mg, 3.45 mmol, 3.00equiv). The resulting solution was stirred overnight at roomtemperature. The reaction mixture was then diluted with 50 mL of water,extracted with 2×150 mL of dichloromethane. The organic layers werecombined, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (2/1). This resulted in 400 mg (65%) of thetitle compound as a brown solid. LC-MS (ES, m/z): 532[M+H]⁺

Step 4.(4-(3′-(5-amino-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-carbonyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

Into a 100-mL round-bottom flask, was placed a solution of tert-butyl(3-(4′-(4-(1-hydroxycyclopropane-1-carbonyl)piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazol-5-yl)carbamate(400 mg, 0.75 mmol, 1.00 equiv) in dichloromethane (30 mL). To the aboveHCl gas was introduced in. The resulting solution was stirred for 1 h atroom temperature. The solids were collected by filtration and dissolvedin 10 mL of water. The pH value was adjusted to 6˜7 with saturatedsodium bicarbonate solution. The solids were collected by filtration.The residue was purified by Flash-Prep-HPLC with the followingconditions (IntelFlash-1):Column, C₁₈ silica gel; mobile phase,CH₃CN/water with 0.1% NH₄HCO₃=1/5 increasing to CH₃CN/water with 0.1%NH₄HCO₃=3/2 within 20 min; Detector, UV 254&220 nm. This resulted in102.9 mg (32%) of the title compound as a white solid. LC-MS (ES, m/z):432[M+H]⁺

Step 1. N-(4-bromophenyl)-3-methyl-4,5,6,7-tetrahydro-1 and 2H-indazole

Into a 250-mL round-bottom flask (1 atm) purged and maintained with aninert atmosphere of nitrogen, was placed 2-acetylcyclohexan-1-one (4.08g, 29.11 mmol, 1.00 equiv), (4-bromophenyl)hydrazine hydrochloride (6.5g, 29.08 mmol, 1.00 equiv), TsOH (500 mg, 2.90 mmol, 0.10 equiv),ethane-1,2-diol (100 mL). The resulting solution was stirred for 2 daysat 105° C. in an oil bath. The resulting mixture was concentrated undervacuum. The crude product (4 g) was purified by Flash-Prep-HPLC with thefollowing conditions (IntelFlash-1):Column, C18 silica gel; mobilephase, 0.05% NH₄HCO₃ solution, MeCN=95/5 increasing to 0.05% NH₄HCO₃solution, MeCN=0/100 within 60 min; Detector, UV 254 nm. 1.5 g productwas obtained. This resulted in 1.5 g (18%) of2-(4-bromophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole as a lightyellow solid and 0.8 g (9%) of1-(4-bromophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole as a lightyellow solid. LC-MS (ES, m/z): 292 [M+H]⁺

Step 2. 1-(4-bromophenyl)-3-methyl-1H-indazole

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed1-(4-bromophenyl)-3-methyl-4,5,6,7-tetrahydro-1H-indazole (3.5 g, 12.02mmol, 1.00 equiv), benzene (100 mL), DDQ (10.9 g, 48.02 mmol, 3.99equiv). The resulting solution was stirred for 22 h at 85° C. in an oilbath. After cooled to room temperature, the resulting mixture wasconcentrated under vacuum and diluted with 200 mL of EA and washed with1×250 mL of water and 3×100 mL of brine. The organic phase was driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(0/100˜10/90). This resulted in 800 mg (23%) of the title compound as awhite solid. LC-MS (ES, m/z) 287, 289 [M+H]⁺

Step 3. tert-butyl4-(4-(3-methyl-1H-indazol-1-yl)benzoyl)piperazine-1-carboxylate

Into a 250-mL pressure tank, was placed1-(4-bromophenyl)-3-methyl-1H-indazole (800 mg, 2.79 mmol, 1.00 equiv),tert-butyl piperazine-1-carboxylate (770 mg, 4.13 mmol, 1.48 equiv),Pd(dppf)Cl₂CH₂Cl₂ (113 mg, 0.14 mmol, 0.05 equiv), toluene (120 mL),triethylamine (837 mg, 8.27 mmol, 2.97 equiv). Then the reactor wasevacuated and back-filled with CO for three times. The resulting mixturewas stirred for 24 h at 130° C. under CO pressure of 20 atm. Aftercooled to room temperature, the resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (0/100˜25/75). This resulted in 1.0 g (85%) ofthe title compound as a light yellow solid. LC-MS (ES, m/z) 421 [M+H]⁺

Step 4. (4-(3-methyl-1H-indazol-1-yl)phenyl)(piperazin-1-yl)methanonehydrochloride

Into a 250-mL round-bottom flask, was placed tert-butyl4-(4-(3-methyl-1H-indazol-1-yl)benzoyl)piperazine-1-carboxylate (1 g,2.38 mmol, 1.00 equiv), dichloromethane (100 mL). Then hydrogen chloride(gas) was introduced in. The resulting solution was stirred for 2 h atroom temperature. The solids were collected by filtration. This resultedin 930 mg (crude) of the title compound as a light yellow solid. LC-MS(ES, m/z) 321 [M+H]⁺

Step 5.(4-(1-hydroxycyclopropane-1-carbonyl)piperazin-1-yl)(4-(3-methyl-1H-indazol-1-yl)phenyl)methanone

Into a 100-mL round-bottom flask, was placed1-hydroxycyclopropane-1-carboxylic acid (265 mg, 2.60 mmol, 1.00 equiv),HBTU (1.086 g, 2.86 mmol, 1.10 equiv), N,N-dimethylformamide (20 mL),(4-(3-methyl-1H-indazol-1-yl)phenyl)(piperazin-1-yl)methanonehydrochloride (930 mg, 2.61 mmol, 1.00 equiv), DIEA (1.68 g, 13.00 mmol,5.01 equiv). The resulting solution was stirred overnight at roomtemperature. The resulting solution was diluted with 100 mL of EA,washed with 3×20 mL of water and 1×20 mL of brine. The organic phase wasdried over anhydrous sodium sulfate and concentrate under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (0/100˜100/0). The collected fractions werecombined and concentrated under vacuum. The resulting solid was stirredin 2×20 mL of MeCN, collected by filtration and dried under reducedpressure. This resulted in 228.5 mg (22%) of the title compound as anoff-white solid. LC-MS (ES, m/z) 405 [M+H]⁺

Step 1.(S)-(4-(4-(tert-butoxycarbonyl)-3-methylpiperazine-1-carbonyl)-3-fluorophenyl)boronicacid

Into a 250 mL round-bottom flash was placed a solution of4-(dihydroxyboranyl)-2-fluorobenzoic acid (1.84 g, 10.00 mmol, 1.00equiv) in DMF (30 mL). HBTU (15.16 g, 39.97 mmol, 4.00 equiv) was addedfollowed by DIEA (1.94 g, 15.01 mmol, 1.50 equiv). The resultingsolution was stirred for 10 min. at RT, then a solution of tert-butyl(2R)-2-methylpiperazine-1-carboxylate (2 g, 9.99 mmol, 1.00 equiv) inDMF (5 mL) was added. The resulting solution was allowed to stirovernight. The solution was then diluted with EtOAc (50 mL) and washedwith brine (3×50 mL). The organic layer was then dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byFCC eluting with dichloromethane/methanol (90:10). This afforded thetitle compound (3.5 g, 96%) as a brown solid. LC-MS (ES, m/z) 367 [M+H]⁺

Step 2. tert-butyl(S)-4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)-2-methylpiperazine-1-carboxylate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of(S)-(4-(4-(tert-butoxycarbonyl)-3-methylpiperazine-1-carbonyl)-3-fluorophenyl)boronicacid (837 mg, 2.29 mmol, 1.00 equiv) in toluene (20 mL),5-bromo-1-methyl-1H-1,3-benzodiazole (400 mg, 1.90 mmol, 0.83 equiv),Pd(PPh₃)₄ (264 mg, 0.23 mmol, 0.10 equiv), sodium carbonate (2M, 10 mL),ethanol (2.8 mL). The resulting mixture was stirred overnight at 95° C.After cooled to room temperature, the resulting solution was dilutedwith 20 mL of H₂O, extracted with 3×30 mL of ethyl acetate. The organiclayers were combined, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with dichloromethane/methanol (90:10). The collected fractionswere combined and concentrated under vacuum. This resulted in 800 mg(77%) of the title compound as a brown solid. LC-MS (ES, m/z) 453 [M+H]⁺

Step 3.(S)-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)(3-methylpiperazin-1-yl)methanonehydrochloride

Into a 100-mL round-bottom flask, was placed a solution of tert-butyl(S)-4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)-2-methylpiperazine-1-carboxylate(800 mg, 1.77 mmol, 1.00 equiv) in dichloromethane (30 mL). To the aboveHCl (gas) was introduced in. The resulting solution was stirred for 2 hat room temperature. The solids were collected by filtration. Thisresulted in 650 mg (95%) of the title compound as a brown solid. LC-MS(ES, m/z) 353 [M+H]⁺

Step 4.(S)-(4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)-2-methylpiperazin-1-yl)(1-hydroxycyclopropyl)methanone

Into a 100-mL round-bottom flask, was placed a solution of(S)-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)(3-methylpiperazin-1-yl)methanonehydrochloride (650 mg, 1.67 mmol, 1.00 equiv) in N,N-dimethylformamide(20 mL), 1-hydroxycyclopropane-1-carboxylic acid (180 mg, 1.76 mmol,1.05 equiv), HBTU (734 mg, 1.94 mmol, 1.16 equiv), DIEA (908 mg, 7.03mmol, 4.20 equiv). The resulting solution was stirred overnight at roomtemperature. The reaction mixture was diluted with 30 mL of EA, washedwith 3×30 mL of water and 30 mL of brine. The organic phase was driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas applied onto a silica gel column with dichloromethane/methanol(90:10). The crude product was further purified by Prep-HPLC with thefollowing conditions (Waters III):Column, Xbridge RP18 5 um, 19*150;mobile phase, water (0.05% NH₄HCO₃) and MeCN (10% CH₃CN up to 70% in 9min); Detector, UV 220&254 nm. This resulted in 203.1 mg (28%) of thetitle compound as a white solid. LC-MS (ES, m/z) 437 [M+H]⁺

Step 1. tert-butyl(S)-(1-(4-(4-(6-fluorobenzo[d]oxazol-2-yl)benzoyl)-2-methylpiperazine-1-carbonyl)cyclopropyl)carbamate

Into a 100-mL round-bottom flask, was placed1-[(tert-butoxy)carbonyl]aminocyclopropane-1-carboxylic acid(Intermediate 2, 400 mg, 1.99 mmol, 0.90 equiv), HBTU (830 mg, 2.19mmol, 1.0 equiv), N,N-dimethylformide (30 mL),(S)-(4-(6-fluorobenzo[d]oxazol-2-yl)phenyl)(3-methylpiperazin-1-yl)methanonehydrochloride (750 mg, 2.21 mmol, 1.00 equiv) and DIEA (514 mg, 3.98mmol, 1.80 equiv). The resulting solution was stirred for 18 h at 25° C.The resulting solution was diluted with 50 mL of EA and washed with 2×50mL of water. The organic layer dried over Na₂SO₄ and concentrated undervacuum. This resulted in 800 mg (crude) of the title compound as ayellow solid. LC-MS (ES, m/z): 523 [M+H]⁺

Step 2.(S)-(4-(1-aminocyclopropane-1-carbonyl)-3-methylpiperazin-1-yl)(4-(6-fluorobenzo[d]oxazol-2-yl)phenyl)methanone

Into a 100-mL round-bottom flask, was placed tert-butyl(S)-(1-(4-(4-(6-fluorobenzo[d]oxazol-2-yl)benzoyl)-2-methylpiperazine-1-carbonyl)cyclopropyl)carbamate(800 mg, 1.53 mmol, 1.00 equiv), dichloromethane (20 mL),tetrahydrofuran (20 mL). Then hydrogen chloride (gas) was bubbled intothe mixture. The resulting solution was stirred for 3 h at 25° C. Theresulting mixture was concentrated under vacuum and dissolved in 10 mLof water. The pH value of the solution was adjusted to 8 with saturatedsodium carbonate solution. The solids were collected by filtration. Thecrude product was purified by Prep-HPLC with the following conditions(Waters I):Column, Xbridge Prep C18 OBD column, 5 um, 19*150 mm; mobilephase, Water (0.05% NH₄HCO₃) and CH₃CN (7% CH₃CN up to 35% in 10 min);Detector, UV 220&254 nm. This resulted in 163.6 mg (25%) of the titlecompound as a white solid. LC-MS (ES, m/z): 423 [M+H]⁺

Step 1. tert-butyl4-(4-(3-aminobenzo[d]isoxazol-6-yl)benzoyl)piperazine-1-carboxylate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of tert-butyl4-[[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl]piperazine-1-carboxylate(Intermediate 3, 1.9 g, 4.56 mmol, 1.00 equiv) in dioxane (100 mL),6-bromo-1,2-benzoxazol-3-amine (1 g, 4.69 mmol, 1.00 equiv), Pd(dppf)Cl₂(344 mg, 0.47 mmol, 0.10 equiv), sodium carbonate (20 mL, 2M). Theresulting solution was stirred overnight at 80° C. After cooled to roomtemperature, the resulting mixture was diluted with DCM, washed withwater and concentrated under vacuum. The residue was applied onto asilica gel column with dichloromethane/methanol (10/1). This resulted in1.6 g (83%) of the title compound as a gray solid. LC-MS (ES, m/z) 423[M+H]⁺

Step 2. tert-butyl4-(4-(3-(cyclopropanecarboxamido)benzo[d]isoxazol-6-yl)benzoyl)piperazine-1-carboxylate

Into a 100 mL round-bottom flask, was placed a solution of tert-butyl4-[[4-(3-amino-1,2-benzoxazol-6-yl)phenyl]carbonyl]piperazine-1-carboxylate(800 mg, 1.89 mmol, 1.00 equiv) in pyridine (20 mL),cyclopropanecarbonyl chloride (199 mg, 1.90 mmol, 1.00 equiv). Theresulting solution was stirred for 2 h at 70° C. After cooled to roomtemperature, the reaction mixture was diluted with EtOAc, washed withwater and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1/1). Thisresulted in 535 mg (58%) of the title compound as a white solid. LC-MS(ES, m/z): 491[M+H]⁺

Step 3.N-(6-(4-(piperazine-1-carbonyl)phenyl)benzo[d]isoxazol-3-yl)cyclopropanecarboxamidehydrochloride

Into a 100-mL round-bottom flask, was placed a solution of tert-butyl4-[[4-(3-cyclopropaneamido-1,2-benzoxazol-6-yl)phenyl]carbonyl]piperazine-1-carboxylate(535 mg, 1.09 mmol, 1.00 equiv) in dichloromethane (30 mL). To the abovehydrogen chloride (g) was introduced in. The resulting solution wasstirred for 1 h at room temperature. The resulting mixture wasconcentrated under vacuum. This resulted in 466 mg (quantitive) of thetitle compound as a white solid. LC-MS (ES, m/z): 391[M+H]⁺

Step 4.N-(6-(4-(4-(1-hydroxycyclopropane-1-carbonyl)piperazine-1-carbonyl)phenyl)benzo[d]isoxazol-3-yl)cyclopropanecarboxamide

Into a 50-mL round-bottom flask, was placed a solution of1-hydroxycyclopropane-1-carboxylic acid (111 mg, 1.09 mmol, 1.00 equiv)in N,N-dimethylformamide (20 mL), HBTU (620 mg, 1.63 mmol, 1.50 equiv),DIEA (563 mg, 4.36 mmol, 4.00 equiv). The above mixture was stirred for1 h at room temperature. To this was addedN-(6-[4-[(piperazin-1-yl)carbonyl]phenyl]-1,2-benzoxazol-3-yl)cyclopropanecarboxamidehydrochloride (466 mg, 1.09 mmol, 1.00 equiv). The resulting mixture wasstirred overnight at room temperature. The reaction mixture was dilutedwith DCM, washed with water and concentrated under vacuum. The residuewas applied onto a silica gel column with dichloromethane/methanol(10/1), and further purified by Prep-HPLC with the following conditions(IntelFlash-1):Column, Cis silica gel; mobile phase, CH₃CN/water with0.05% NH₄HCO₃=40% increasing to CH₃CN/water with 0.05% NH₄HCO₃=60%within 15 min; Detector, UV 254&220 nm. This resulted in 123.9 mg (24%)of the title compound as a white solid. LC-MS (ES, m/z): 475[M+H]⁺

Step 1. tert-butyl4-(3′-amino-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate

To a 100 mL flask was added tert-butyl piperazine-1-carboxylate (1.310g, 7.03 mmol), 3′-aminobiphenyl-4-carboxylic acid (1.5 g, 7.03 mmol) andDIEA (2.457 ml, 14.07 mmol) in DMF (25 ml) followed by HBTU (3.20 g,8.44 mmol) to give a brown suspension. This was stirred at RT for 8 hrs.Water (50 mL) was added and the reaction was extracted twice withmethylene chloride (2×100 mL). The organic layers were combined andwashed with water (25 mL) and brine (25 mL). The organic layer was thendried over magnesium sulfate, filtered and concentrated in vacuo. Thecrude residue was purified by FCC (0-4% MeOH/CH₂Cl₂) affording the titlecompound (1.70 g, 63%) as a yellow solid. LC-MS (ES, m/z): 382[M+H]⁺

Step 2 (RCOCl). tert-butyl4-(3′-(cyclopentanecarboxamido)-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate

In a 20 mL scintillation vial was added tert-butyl4-(3′-aminobiphenylcarbonyl)piperazine-1-carboxylate (150 mg, 0.393mmol), pyridine (0.095 ml, 1.180 mmol), and cyclopentanecarbonylchloride (0.057 ml, 0.472 mmol) in THF (9 ml) to give an light yellowsuspension. This was stirred at RT for 2 hours. The reaction was takenup in 75 mls of methylene chloride. The organic solution was washedtwice with dilute sodium bicarbonate solution (aq, 35 mL) and once withbrine (15 mL). The organic layer was then dried over magnesium sulfate,filtered and concentrated in vacuo. The crude product was purified byFCC (0-60% EtOAc/hexanes) affording the title compound (116 mg, 62%).LC-MS (ES, m/z): 478[M+H]⁺

Step 2 (RCO₂H). tert-Butyl4-(3′-(3,3-difluorocyclobutanecarboxamido)biphenylcarbonyl)piperazine-1-carboxylate

In a 20 mL scintillation vial was added tert-butyl4-(3′-aminobiphenylcarbonyl)piperazine-1-carboxylate (200 mg, 0.524mmol), 3,3-difluorocyclobutanecarboxylic acid (86 mg, 0.629 mmol) andHunig's Base (0.275 ml, 1.573 mmol) in DMF (5 ml) followed by HBTU (239mg, 0.629 mmol) to give a brown suspension. This was stirred at RTovernight and then the reaction was diluted with water (20 mL). Thereaction mixture was then extracted with methylene chloride (2×40 mL).The combined organic layers were washed with water (20 mL) and brine (20mL). The organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The crude product was purified by FCC (0-60%EtOAc/hexanes) affording the title compound as a foamy glass. LC-MS (ES,m/z): 500[M+H]⁺

Step 3.N-(4′-(piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)cyclopentanecarboxamide2,2,2-trifluoroacetate

In a 100 mL round-bottomed flask was added tert-butyl4-(3′-(cyclopentanecarboxamido)biphenylcarbonyl)piperazine-1-carboxylate(114 mg, 0.239 mmol) in methylene chloride (15 ml) to give a yellowsuspension. Trifluoroacetic acid (0.552 mls, 7.16 mmol) was addedgradually by syringe. The solution was stirred at RT for 2.5 hours. Thesolution was concentrate and the crude product was triturated with etherand then decanted. The resulting solid was dried in vacuo affording thetitle compound (117 mg, 100%) as a foamy solid. LC-MS (ES, m/z):378[M+H]⁺

Step 4.N-(4′-(4-(1-hydroxycyclopropane-1-carbonyl)piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)cyclopentanecarboxamide

In a 100 mL round-bottomed flask was addedN-(4′-(piperazine-1-carbonyl)biphenyl-3-yl)cyclopentanecarboxamide2,2,2-trifluoroacetate (118 mg, 0.24 mmol),1-hydroxycyclopropanecarboxylic acid (19.60 mg, 0.192 mmol) and pyridine(0.058 ml, 0.720 mmol) in DMF (5 ml) followed by HBTU (127 mg, 0.336mmol) to give a yellow suspension. This was stirred at RT for 4.5 hours.Hunig's base was added (0.021 mL, 0.12 mmols) and the stirring wascontinued. After 18 hours additional Hunig's base (0.063 mL, 0.36 mmols)was added and the reaction solution was stirred overnight. The reactionwas diluted with water (20 mL) and extracted with methylene chloride(2×50 mL). The organic layers were combined and washed with water (10mL) and brine (10 mL). The solvent was dried over magnesium sulfate,filtered and concentrated in vacuo. The crude product was purified byFCC (0-7% MeOH/CH₂Cl₂) affording the title compound (35.5 mg, 29%) as anoff-white solid. LC-MS (ES, m/z): 462[M+H]⁺

Step 1. tert-Butyl4-(4′-bromo-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate

To a suspension of 4′-bromo-[1,1′-biphenyl]-4-carboxylic acid (1.5 g,5.4 mmol) in DMF (35 mL) was added TEA (1.21 mL, 8.6 mmol), followed bytert-butyl piperazine-1-carboxylate (1.11 g, 6.0 mmol) and HATU (2.6 g,6.8 mmol). The reaction mixture was stirred at room temperatureovernight then diluted with water and extracted with EtOAc. Organicphase was washed with water, 5% acetic acid, saturated NaHCO₃, brine,dried over Na₂SO₄ and concentrated under reduced pressure. The crudematerial was chromatographed on a silica gel column eluting with agradient of EtOAc in CH₂Cl₂ to afford 2.0 g (83% yield) of the titlecompound.

Step 2.tert-Butyl4-(4′-(1H-pyrazol-4-yl)-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate

tert-Butyl4-(4′-bromo-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate (1.0 g,2.3 mmol), (1H-pyrazol-4-yl)boronic acid (as HCl salt, 0.67 g, 4.5 mmol)and 2M K₃PO₄ (aq) (4.5 mL, 9.0 mmol) were mixed with 30 mL of DMF in amicrowave tube. The resulting mixture was vacuumed several times andrefilled with argon before adding Pd(PPh₃)₄ (0.39 g, 0.3 mmol). Thereaction mixture was microwaved for 35 min at 150° C. After cooling toroom temperature, the reaction mixture was diluted with water andsaturated NaHCO₃ and extracted with MeOH/CHCl₃ mixture of solvents.Organic phase was dried over Na₂SO₄ and concentrated under reducedpressure. The crude was purified twice by ISCO (24 g silica gel column)eluting with a gradient of 0.7 N NH₃/MeOH in CHCl₃ to afford 160 mg(˜17% yield) of the desired product.

Step 3.(4′-(1H-pyrazol-4-yl)-[1,1′-biphenyl]-4-yl)(piperazin-1-yl)methanone,HCl salt

tert-Butyl4-(4′-(1H-pyrazol-4-yl)-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate(160 mg, 0.37 mmol) was dissolved in 18 mL of anhydrous MeOH saturatedwith HCl (gas) at 0° C. and was stirred at room temperature for ˜3 h.The resulting solution was concentrated to dryness under reducedpressure. The residue was triturated with 2% MeOH in Et₂O followed byEt₂O and pentane to afford 150 mg (quant. yield) of the title compoundas the hydrochloride salt which was used in the next step withoutfurther purification.

Step 4.(4-(4′-(1H-pyrazol-4-yl)-[1,1′-biphenyl]-4-carbonyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

To a solution of(4′-(1H-pyrazol-4-yl)-[1,1′-biphenyl]-4-yl)(piperazin-1-yl)methanone,HCl salt (150 mg, 0.37 mol) and 1-hydroxycyclopropane-1-carboxylic acid(69 mg, 0.56 mmol) in 3 mL of DMF was added HBTU (230 mg, 0.6 mmol),followed by addition of DIEA (0.33 mL, 1.8 mmol). The resulting solutionwas stirred overnight at room temperature. The reaction mixture wasdiluted with water and saturated NaHCO₃ and extracted several times withEtOAc/MeOH and MeOH/CHCl₃ mixture of solvents. The organic layers werecombined, washed with water, brine, dried over Na₂SO₄ and concentratedunder reduced pressure. The crude was purified by ISCO twice (24 gsilica gel gold column) eluting with a gradient of 0.7 N NH₃/MeOH inEtOAc and 0.7 N NH₃/MeOH in CHCl₃. The product obtained afterchromatography was triturated in Et₂O to afford 110 mg (71% yield) ofthe pure target compound. LC-MS (ES, m/z): 417[M+H]⁺

Step 1. tert-Butyl4-(4-bromo-2,6-difluorobenzoyl)piperazine-1-carboxylate

To a solution of 4-bromo-2,6-difluorobenzoic acid (1.00 g, 4.22 mmol),tert-butyl piperazine-1-carboxylate (0.786 g, 4.22 mmol), and HBTU(1.925 g, 5.06 mmol) in DMF (10.0 ml) was added DIEA (2.95 ml, 16.88mmol). The reaction was stirred at room temperature overnight. Saturatedsodium bicarbonate (aqueous, 10 mL) was added followed by water (10 mL).The reaction solution was then extracted several times with EtOAc (3×20mL). The organic extracts were pooled and washed with water (2×20 mL)and brine (20 mL). The organic layer was dried over sodium sulfate,filtered and concentrated in vacuo providing the crude product as anorange oil. The crude product was subjected to FCC (Biotage SNAP 25;eluent: 15%-25% EtOAc in hexanes over 10 CV). This afforded the titlecompound (1.44 g, 86%) as an off-white solid. LC-MS (ES, m/z): 405[M+H]⁺

Step 2. tert-Butyl4-(2,6-difluoro-4-(1-methyl-1H-indazol-6-yl)benzoyl)piperazine-1-carboxylate

tert-Butyl 4-(4-bromo-2,6-difluorobenzoyl)piperazine-1-carboxylate(383.2 mg, 0.946 mmol), 1-methyl-1H-indazol-6-ylboronic acid (166 mg,0.946 mmol) and potassium phosphate (1.00 g, 4.73 mmol) were suspendedin a nitrogen purged solution of Dioxane (6.0 ml) and Water (1.2 ml).The reaction mixture was further purged with nitrogen for 5 minutes.Palladium Tetrakis (109 mg, 0.095 mmol) was added and the reactionsolution was purged with nitrogen for 5 more minutes. The mixture wassubjected to microwave irradiation at 130° C. for 30 minutes resultingin a yellow biphasic solution. The organic layer (top) was removed,filtered through celite and concentrated in vacuo to afford the crudeproduct as a light red powder. The crude product was subjected to FCC(Biotage SNAP 25; Gradient Eluent: 0-20% MeOH in in EtOAc with 0.5%triethylamine over 15 CV). This afforded the title compound (327 mg,76%) as a light beige powder. LC-MS (ES, m/z): 421[M+H]⁺

Step 3.(2,6-difluoro-4-(1-methyl-1H-indazol-6-yl)phenyl)(piperazin-1-yl)methanonehydrochloride

HCl (4N in 1,4-dioxane) (0.106 ml, 3.51 mmol) was added to a solution oftert-butyl4-(2,6-difluoro-4-(1-methyl-1H-indazol-6-yl)benzoyl)piperazine-1-carboxylate(320.0 mg, 0.701 mmol) in Dioxane (4.0 ml). The reaction solution wasstirred at room temperature for 2 hours resulting in the formation of awhite precipitate. Ether (10 mL) was added to the reaction and theprecipitate was then collected by filtration. The precipitate wasfurther washed with ether (10 mL), collected and dried in vacuoaffording the title compound (275 mg, 100%) as a white powder. LC-MS(ES, m/z): 356[M+H]⁺

Step 4.(4-(2,6-difluoro-4-(1-methyl-1H-indazol-6-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

To a solution of(2,6-difluoro-4-(1-methyl-1H-indazol-6-yl)phenyl)(piperazin-1-yl)methanonehydrochloride (218.3 mg, 0.556 mmol), 1-hydroxycyclopropanecarboxylicacid (56.7 mg, 0.556 mmol), and HBTU (254 mg, 0.667 mmol) in DMF (4.0ml) was added DIEA (0.388 ml, 2.223 mmol). The reaction was stirred atroom temperature overnight. Saturated sodium bicarbonate (aqueous, 10mL) was added followed by water (10 mL). The reaction solution was thenextracted several times with EtOAc (3×20 mL). The organic extracts werepooled and washed with water (2×20 mL) and brine (20 mL). The organiclayer was dried over sodium sulfate, filtered and concentrated in vacuoproviding the crude product as an orange oil. The crude product wassubjected to FCC (Biotage SNAP 25; eluent: 20-10% hexanes in EtOAc over10 CV). The product was then subjected to an additional purification viaFCC (Biotage SNAP 25; gradient eluent: 5-15% MeOH in methylenechloride). This afforded the title compound (105.2 mg, 43%) as a whitepowder. LC-MS (ES, m/z): 441[M+H]⁺

Step 1. tert-Butyl 4-(3′-nitrobiphenylcarbonyl)piperazine-1-carboxylate

To a solution of tert-butyl 4-(4-bromobenzoyl)piperazine-1-carboxylate(1.00 g, 2.71 mmol), 3-nitrophenylboronic acid (0.452 g, 2.71 mmol) andpotassium phosphate (2.87 g, 13.54 mmol) in nitrogen bubbled dioxane(10.0 ml) and nitrogen bubbled Water (2.0 ml) was added palladiumtetrakis (0.313 g, 0.271 mmol). The reaction solution was furtherbubbled with a stream of nitrogen for 15 minutes. The reaction was thenrun overnight at 80° C. The reaction was cooled to room temperatureresulting in a yellow precipitate. The precipitate was collected viafiltration. The precipitate was then washed with methanol (20 mL) andether (10 mL). This afforded the title compound (1.0 g, 92%) as a lightyellow powder. LC-MS (ES, m/z): 412[M+H]⁺

Step 2. tert-Butyl 4-(3′-aminobiphenylcarbonyl)piperazine-1-carboxylate

A mixture of tert-butyl4-(3′-nitrobiphenylcarbonyl)piperazine-1-carboxylate (1.00 g, 2.430mmol) and palladium hydroxide on activated carbon (0.341 g, 2.430 mmol)was suspended in MeOH (30 ml). The bomb was placed on a Parr Shaker andcharged with hydrogen gas at 30 psi. The reaction was allowed to shakefor 3 hours. The reaction was then vented with nitrogen, filteredthrough celite and concentrated in vacuo affording the title compound(924 mg, 100%) as a light brown solid. LC-MS (ES, m/z): 382[M+H]⁺

Step 3. tert-Butyl4-(3′-(cyclobutanesulfonamido)biphenylcarbonyl)piperazine-1-carboxylate

To a solution of tert-butyl4-(3′-aminobiphenylcarbonyl)piperazine-1-carboxylate (500.0 mg, 1.311mmol) in anhydrous pyridine (6.5 ml) was added cyclobutanesulfonylchloride (203 mg, 1.311 mmol) at 40° C. The reaction solution (redcolor) was stirred at 40° C. for 2 days. The reaction solution wascooled to room temperature and diluted with water (10 mL). The solutionwas then extracted several times with EtOAc (3×20 mL). The organicextracts were pooled and washed with 1M citric acid (aqueous, 20 mL),water (20 mL) and brine (20 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo. The crude product wassubjected to FCC (Biotage SNAP 50; gradient eluent: 40-50% EtOAc inhexanes over 15 CV). This afforded the title compound (173 mg, 26.3%) asa white powder. LC-MS (ES, m/z): 500[M+H]⁺

Step 4.N-(4′-(piperazine-1-carbonyl)biphenyl-3-yl)cyclobutanesulfonamidehydrochloride

Hydrogen chloride (4.0N in 1,4-dioxane) (0.438 ml, 1.751 mmol) was addedto a solution of tert-butyl4-(3′-(cyclobutanesulfonamido)biphenylcarbonyl)piperazine-1-carboxylate(175.0 mg, 0.350 mmol) in Dioxane (2.0 ml). The reaction solution wasstirred at room temperature for 3 hours resulting in the formation of aoff-white precipitate. Ether (10 mL) was added to the reaction and theprecipitate was then collected by filtration. The precipitate wasfurther washed with ether (10 mL), collected and dried in vacuoaffording the title compound (153 mg, 100%) as an off-white powder.LC-MS (ES, m/z): 400[M+H]⁺

Step 5.N-(4′-(4-(1-hydroxycyclopropanecarbonyl)piperazine-1-carbonyl)biphenyl-3-yl)cyclobutanesulfonamide

To a solution ofN-(4′-(piperazine-1-carbonyl)biphenyl-3-yl)cyclobutanesulfonamidehydrochloride (164.5 mg, 0.377 mmol), 1-hydroxycyclopropanecarboxylicacid (38.5 mg, 0.377 mmol), and HBTU (172 mg, 0.453 mmol) in DMF (2.0ml) was added DIEA (0.264 ml, 1.509 mmol). The reaction was stirred atroom temperature overnight. Saturated sodium bicarbonate (aqueous, 10mL) was added followed by water (10 mL). The reaction solution was thenextracted several times with EtOAc (3×20 mL). The organic extracts werepooled and washed with water (2×20 mL) and brine (20 mL). The organiclayer was dried over sodium sulfate, filtered and concentrated in vacuoproviding the crude product as an orange oil. The crude product wassubjected to FCC (Biotage SNAP 25; eluent: 100% EtOAc over 10 CV)followed by an additional FCC purification (Biotage SNAP 25; gradienteluent: 0-5% MeOH in methylene chloride). This afforded the titlecompound (55 mg, 30.3%) as a glassy clear solid. LC-MS (ES, m/z):484[M+H]⁺

Step 1. tert-Butyl4-(3′-(cyclobutylmethylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate

To an ice-cold solution of tert-butyl4-(3′-amino-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate (300 mg,0.79 mmol) in pyridine (4 mL) cyclobutylmethanesulfonyl chloride (200mg, 1.2 mmol) was added dropwise. The resulting mixture was allowed towarm up to room temperature over 4 h then concentrated and kept on ahigh vacuum line overnight. The residue was dissolved in EtOAc, washedwith water, 5% acetic acid, saturated NaHCO₃, brine, dried over Na₂SO₄and concentrated under reduced pressure. The crude material waschromatographed on a silica gel column eluting with a gradient of EtOAcin CH₂Cl₂ to obtain 295 mg (73% yield) of the title compound.

Step 2 (HCl).1-cyclobutyl-N-(4′-(piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)methanesulfonamidehydrogen chloride

tert-Butyl4-(3′-(cyclobutylmethylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate(295 mg, 0.57 mmol) was dissolved in 18 mL of anhydrous MeOH saturatedwith HCl (gas) and stirred at room temperature for ˜3 h. The resultingsolution was concentrated to dryness under reduced pressure. The residuewas triturated with 2% MeOH in Et₂O followed by trituration with Et₂Oand dried to afford 200 mg (78% yield) of the title compound as thehydrochloride salt which was used for the next step without furtherpurification.

Step 2 (TFA).N-(4′-(Piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)tetrahydro-2H-pyran-4-sulfonamidetrifluoroacetate

To a solution of tert-butyl4-(3′-(tetrahydro-2H-pyran-4-sulfonamido)-[1,1′-biphenyl]-4-carbonyl)-piperazine-1-carboxylate(70 mg, 0.13 mmol) in DCM (3 mL) was added TFA (0.5 mL). The mixture wasstirred at room temperature for 2 hours. After removal of solvents underreduced pressure, the crude title compound (69 mg, 100%) was useddirectly in the next step without further purification.

Step 3.1-cyclobutyl-N-(4′-(4-(1-hydroxycyclopropanecarbonyl)piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)methanesulfonamide

To a solution of1-cyclobutyl-N-(4′-(piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)methanesulfonamidehydrogen chloride (295 mg, 0.45 mol) and1-hydroxycyclopropane-1-carboxylic acid (77 mg, 0.76 mmol) in 3 mL ofDMF was added HBTU (300 mg, 0.81 mmol) followed by an addition of DIEA(0.42 mL, 2.4 mmol). The resulting solution was stirred at roomtemperature overnight. The reaction mixture was diluted with water andsatu. NaHCO₃ and extracted several times with CH₂Cl₂ and MeOH/CHCl₃mixture of solvents. The organic layers were combined, washed withwater, brine, dried over Na₂SO₄ and concentrated under reduced pressure.The crude material was twice purified by ISCO (40 g silica gel goldcolumn) eluting with a gradient of MeOH in CH₂Cl₂ and then triturated in2-3% MeOH in Et₂O to afford 129 mg (58% yield) of the title compound.LC-MS (ES, m/z): 498[M+H]⁺

Step 1. tert-butyl(1-(4-(2-fluoro-4-(2-methyl-1H-indol-1-yl)benzoyl)piperazine-1-carbonyl)cyclopropyl)carbamate

Into a 100-mL round-bottom flask was placed1-[3-fluoro-4-[(piperazin-1-yl)carbonyl]phenyl]-2-methyl-1H-indolehydrochloride (Intermediate 4, 600 mg, 1.60 mmol, 1.00 equiv),1-[[(tert-butoxy)carbonyl]amino]cyclopropane-1-carboxylic acid (322 mg,1.60 mmol, 1.00 equiv), N,N-dimethylformamide (40 mL), HBTU (729 mg,1.92 mmol, 1.20 equiv), DIEA (828 mg, 6.41 mmol, 3.99 equiv). Theresulting solution was stirred overnight at room temperature. Thereaction mixture was diluted with 50 mL of EA, washed with 3×50 mL ofwater and 50 mL of brine. The organic phase was concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (70:30). This resulted in 300 mg (36%) of thetitle compound as a yellow solid. LC-MS (ES, m/z): 521[M+H]⁺

Step 2.(4-(1-aminocyclopropane-1-carbonyl)piperazin-1-yl)(2-fluoro-4-(2-methyl-1H-indol-1-yl)phenyl)methanone

Into a 100-mL round-bottom flask, was placed tert-butylN-[1-[(4-[[2-fluoro-4-(2-methyl-1H-indol-1-yl)phenyl]carbonyl]piperazin-1-yl)carbonyl]cyclopropyl]carbamate(300 mg, 0.58 mmol, 1.00 equiv), dichloromethane (20 mL),trifluoroacetic acid (5 mL). The resulting solution was stirredovernight at room temperature. The resulting mixture was concentratedunder vacuum. The residue was purified by Prep-HPLC with the followingconditions (Waters I):Column, SunFire Prep C18, 5 um, 19*100 mm; mobilephase, Water (0.05% NH₄HCO₃) and CH₃CN (65% CH₃CN up to 85% in 7 min);Detector, UV 220&254 nm. This resulted in 73.3 mg (30%) of the titlecompound as a white solid. LC-MS (ES, m/z): 421[M+H]⁺

Step 1. tert-butyl4-(6-hydroxynaphthalen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

Into a 250 mL round bottom flash was placed 6-bromonaphthalen-2-ol (2 g,8.97 mmol, 1.00 equiv), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(2.7 g, 8.70 mmol, 1.00 equiv), potassium carbonate (3.6 g, 26.05 mmol,3.00 equiv), and Pd(dppf)Cl₂ (100 mg, 0.14 mmol, 0.01 equiv) in1,4-dioxane (30 mL) and water (10 mL). The resulting solution wasstirred overnight at 110° C. in an oil bath. The reaction mixture wascooled, diluted with EtOAc (120 mL) and washed with brine (2×100 mL).The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo. The crude product was purified by silica gelchromatography eluting with dichloromethane/methanol (50:1). Thisresulted in 1.9 g (65%) of the title compound as a yellow solid. LC-MS(ES, m/z): 326[M+H]⁺

Step 2. tert-butyl 4-(6-hydroxynaphthalen-2-yl)piperidine-1-carboxylate

Into a 250 mL round bottom flask was placed tert-butyl4-(6-hydroxynaphthalen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.9g, 5.84 mmol, 1.00 equiv), ethanol (50 mL), and 10% palladium on carbon(0.5 g). To this suspension was charged in hydrogen gas. The resultingsolution was stirred for 2 hours at r.t. The solids were filtered outand the solution was concentrated in vacuo affording the title compound(1.9 g, 99%) as a light yellow solid. LC-MS (ES, m/z): 328[M+H]⁺

Step 3. tert-butyl4-(6-(((trifluoromethyl)sulfonyl)oxy)naphthalen-2-yl)piperidine-1-carboxylate

Into a 100 mL round bottom flask was placed tert-butyl4-(6-hydroxynaphthalen-2-yl)piperidine-1-carboxylate (1.9 g, 5.79 mmol,1.00 equiv), dichloromethane (20 mL), 2,6-lutidine (3.4 mL, 3.00 equiv)and triflic anhydride (1.5 mL, 1.50 equiv). The resulting solution wasstirred at −40° C. for 10 minutes and then slowly warmed to r.t. over 2hours. The reaction was quenched via the addition of water (100 mL). Theorganic layer was then washed with brine (2×100 mL) and 5% hydrochloricacid (2×50 mL). The organic layer was dried over sodium sulfate,filtered and concentrated in vacuo. The crude product was purified bysilica gel chromatography eluting with EtOAc/petroleum ether (1:5). Thisresulted in 2.1 g (79%) of the title compound as a white solid. LC-MS(ES, m/z): 461[M+H]⁺

Step 4. tert-butyl 4-(6-cyanonaphthalen-2-yl)piperidine-1-carboxylate

Into a 30 mL vial was placed tert-butyl4-(6-(((trifluoromethyl)sulfonyl)oxy)naphthalen-2-yl)piperidine-1-carboxylate(1.5 g, 3.26 mmol, 1.00 equiv), zinc cyanide (840 mg, 7.15 mmol, 2.20equiv), and Pd(dppf)Cl₂ (100 mg, 0.14 mmol, 0.04 equiv) in DMF (10 mL).The resulting solution was subjected to microwave irradiation at 160° C.for 15 minutes. The reaction was cooled, diluted with 100 mL of EtOAcand washed with water (2×100 mL) and brine (2×50 mL). The organic layerwas dried over sodium sulfate, filtered and concentrated in vacuo. Thecrude product was purified by silica gel chromatography eluting withEtOAc/petroleum ether (1:10). This resulted in 1.0 g (91%) of the titlecompound as a white solid. LC-MS (ES, m/z): 337[M+H]⁺

Step 5. 6-(piperidin-4-yl)-2-naphthonitrile hydrochloride

Into a 100 mL round bottom flask was placed tert-butyl4-(6-cyanonaphthalen-2-yl)piperidine-1-carboxylate (1.0 g, 2.97 mmol,1.00 equiv) in dichloromethane (20 mL). HCl (g) was bubbled into thereaction solution and stirred for 30 minutes at r.t. resulting in aprecipitate. The solid was collected and dried in vacuo affording thetitle compound (0.7 g, 100%) as a white solid. LC-MS (ES, m/z):237[M+H]⁺

Step 6. tert-butyl4-(4-(6-cyanonaphthalen-2-yl)piperidine-1-carbonyl)piperazine-1-carboxylate

Into a 100 mL round bottom flask was placed6-(piperidin-4-yl)-2-naphthonitrile hydrochloride, triphosgene (1.0 g,3.37 mmol, 1.10 equiv), Et₃N (1.8 mL, 4.80 equiv) in dichloromethane (20mL). The reaction was stirred for 2 hours and then pyridine (0.35 mL,1.50 equiv) and tert-butyl piperazine-1-carboxylate (700 mg, 3.76 mmol,1.20 equiv) were added. The resulting solution was stirred overnight atr.t. The reaction mixture was then washed with water (2×100 mL) andbrine (2×50 mL). The organic layer was dried over sodium sulfate,filtered and concentrated in vacuo affording the title compound (0.8 g,60%) as a yellow solid. LC-MS (ES, m/z): 449[M+H]⁺

Step 7. 6-(1-(piperazine-1-carbonyl)piperidin-4-yl)-2-naphthonitrilehydrochloride

Into a 100 mL round bottom flask was placed tert-butyl4-(4-(6-cyanonaphthalen-2-yl)piperidine-1-carbonyl)piperazine-1-carboxylate(800 mg, 1.78 mmol, 1.00 equiv) in dichloromethane (15 mL). HCl (g) wasbubbled into the reaction solution and stirred for 2 hours at r.t. Thereaction solution was concentrated in vacuo affording the title compound(0.6 g, 97%) as a white solid. LC-MS (ES, m/z): 349[M+H]⁺

Step 8.6-(1-(4-(1-hydroxycyclopropane-1-carbonyl)piperazine-1-carbonyl)piperidin-4-yl)-2-naphthonitrile

Into a 100 mL round bottom flask was placed1-hydroxycyclopropane-1-carboxylic acid (180 mg, 1.76 mmol, 1.00 equiv),HBTU (900 mg, 2.37 mmol, 2.30 equiv), and6-(1-(piperazine-1-carbonyl)piperidin-4-yl)-2-naphthonitrilehydrochloride (600 mg, 1.72 mmol, 1.00 equiv) in DMF (15 mL). DIEA (0.8mL, 5.00 equiv) was added and the resulting solution was stirredovernight at r.t. The reaction solution was then diluted with 100 mL ofEtOAc and washed with water (2×100 mL) and brine (2×50 mL). The organiclayer was then dried over sodium sulfate, filtered and concentrated invacuo. The crude product was purified by silica gel chromatographyeluting with dichloromethane/methanol (20:1) and then subjected toPrep-HPLC with the following conditions conditions (Waters I):Column,Xbridge Prep Cl₈ OBD column, 5 um, 19*150 mm; mobile phase, Water (0.05%NH₄HCO₃) and CH₃CN (33% CH₃CN up to 38% in 12 min). This resulted in106.9 mg (14%) of the title compound as a white solid. LC-MS (ES, m/z):433 [M+H]⁺

Intermediates

tert-Butyl4-(4-(2-oxo-1,2-dihydroquinolin-3-yl)benzoyl)piperazine-1-carboxylate

Tetrakis(triphenylphosphine)palladium(O) (0.078 g, 0.068 mmol) was addedto a mixture of tert-butyl 4-(4-bromobenzoyl)piperazine-1-carboxylate(0.250 g, 0.677 mmol), 2-fluoroquinolin-3-ylboronic acid (0.129 g, 0.677mmol), and sodium carbonate (0.287 g, 2.71 mmol) in dioxane (5.0 mL) andwater (1.0 mL). The mixture stirred in the microwave at 60° C. for 1.5h. The reaction mixture was filtered and concentrated to afford a yellowoil. This material was purified via column chromatography on silica gel(Biotage 25 g column, gradient elution with 50-100% ethylacetate-hexane) to afford tert-butyl4-(4-(2-oxo-1,2-dihydroquinolin-3-yl)benzoyl)piperazine-1-carboxylate(0.228 g, 0.526 mmol, 78% yield) as a white solid. MS (ESI, pos. ion)m/z: 434 (M+1).

5-bromopicolinoyl chloride

Thionyl chloride (10 ml, 137 mmol) was added to 5-bromopicolinic acid(5.00 g, 24.75 mmol). A drop of DMF was added, and the mixture washeated at 80° C. for 2 h. The excess thionyl chloride was removed toafford 5-bromopicolinoyl chloride (5.413 g, 24.55 mmol, 99% yield) as apale yellow solid. An aliquot was quenched with methanol to affordmethyl 5-bromopicolinate. MS (ESI, pos. ion) m/z: 216, 218 (M+1).

5-bromo-1H-indole-2-carbonitrile Step 1. 5-bromo-1H-indole-2-carboxamide

5-bromo-1H-indole-2-carboxylic acid (0.75 g, 3.12 mmol) was added todichloromethane (10 mL) to give a suspension. Thionyl chloride (0.616mL, 8.44 mmol) was added gradually by syringe. A drop of DMF was addedand the suspension was heated at reflux for 2.5 h. The mixture wascooled to room temperature and then poured with stirring into 5 Nammonium hydroxide (20 mL, 100 mmol) in 18 mL of ice. The precipitatewas stirred for 2 h. The aqueous emulsion was diluted and then extractedtwice with ethyl acetate. Drying over MgSO₄ and concentrating yielded ayellow crude solid. This was triturated with hexanes, filtered, washedwith hexanes, and dried to afford 5-bromo-1H-indole-2-carboxamide (0.81g, 3.15 mmol, 93% yield) as a tan solid. MS (ESI, pos. ion) m/z: 239,241 (M+1)

Step 2. 5-bromo-1H-indole-2-carbonitrile

5-bromo-1H-indole-2-carboxamide (0.68 mg, 2.84 mmol) was added totoluene (20 mL) to give a suspension. Phosphorus oxychloride (1.326 mL,14.22 mmol) was added gradually by syringe. The suspension was heated atreflux for 1.5 h. The reaction was poured into saturated NaHCO₃ andallowed to quench. The layers were extracted twice with 50 mL ofdichloromethane. The combined layers were washed with 20 mL of brine,dried over MgSO₄, and concentrated to yield the crude product. Thismaterial was purified via column chromatography on silica gel (Biotage25 g column, gradient elution with 0-5% ethyl acetate/dichloromethane)to afford 5-bromo-1H-indole-2-carbonitrile (0.408 g, 1.85 mmol, 65%) asa tan solid. MS (ESI, neg. ion) m/z 219/221

tert-butyl 4-(5-bromopyrimidine-2-carbonyl)piperazine-1-carboxylateStep 1. 5-bromopyrimidine-2-carbonyl chloride

Thionyl chloride (3.96 mL, 54.2 mmol) was added to5-bromopyrimidine-2-carboxylic acid (2.0 g, 9.85 mmol). A drop of DMFwas added, and the mixture was heated at 80° C. for 2 hours. The excessthionyl chloride was removed in vacuo to afford5-bromopyrimidine-2-carbonyl chloride as a pale yellow solid. Thematerial was used without purification in the next step.

Step 2. tert-butyl4-(5-bromopyrimidine-2-carbonyl)piperazine-1-carboxylate

5-Bromopyrimidine-2-carbonyl chloride (2.181 g, 9.85 mmol) andN,N-diisopropylethylamine (5.16 mL, 29.6 mmol) were taken up solution inDMF (30 mL). tert-Butyl piperazine-1-carboxylate was added and thereaction mixture stirred for 1.25 h. Water (100 mL) was added and themixture was stirred. The aqueous mixture was then extracted twice with100 mL of ethyl acetate. The second was an emulsion but saturating withNaCl separated the phases. The combined organic phases were washed oncewith brine, dried over MgSO₄, and concentrated. The crude was purifiedvia column chromatography on silica gel (Biotage, gradient elution with0-10% methanol/dichloromethane) to afford tert-butyl4-(5-bromopyrimidine-2-carbonyl)piperazine-1-carboxylate (3.1 g, 7.93mmol, 81%) as a light tan solid. MS (ESI, pos. ion) m/z: 371/373 (M+1)

2-chloro-4-(5-(cyclopropanesulfonamido)pyridin-3-yl)benzoic acid Step 1.N-(5-bromopyridin-3-yl)cyclopropanesulfonamide

5-Bromopyridin-3-amine (0.304 mL, 3.0 mmol) and pyridine (0.534 mL, 1.1mmol) were combined in dichloromethane (15 ml) to give a brown solution.Cyclopropanesulfonyl chloride (0.973 mL, 9.00 mmol) was added graduallyby syringe. This was stirred at rt for 1 day. Additional pyridine (3.0mmol) and 1 equivalent of cyclopropanesulfonyl chloride (3.00 mmol) wereadded. After an additional 1 day the reaction was complete. The reactionwas diluted with 75 mL of dichloromethane and washed with 40 mL ofsaturated NaHCO₃. The aqueous layer was extracted with 10 mL ofdichloromethane and the combined organic phases were washed with 20 mLof brine. The solvent was then dried with MgSO₄ and concentrated. Thecrude product was purified via column chromatography on silica gel(Biotage 100 g column, gradient elution with 0-50% ethylacetate/hexanes) to affordN-(5-bromopyridin-3-yl)cyclopropanesulfonamide (0.81 mgs, 2.92 mmol,73%) as a peach colored solid. MS (ESI, pos. ion) m/z: 277, 279 (M+1).

Step 2. 2-chloro-4-(5-(cyclopropanesulfonamido)pyridin-3-yl)benzoic acid

N-(5-bromopyridin-3-yl)cyclopropanesulfonamide (0.810 g, 2.92 mmol),sodium carbonate (1.24 g, 11.69 mmol) and2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid(0.991 g, 3.51 mmol) were combined in 1,4-dioxane (32 mL) and water (6.4mL) followed by tetrakis(triphenylphosphine)palladium (0) (0.34 g, 0.292mmol) to give a light yellow suspension. The suspension was placed undernitrogen and heated for 16 h at 80° C. The reaction was filtered throughCelite and the solids washed with 1,4-dioxane followed by ethyl acetate.Concentrating the solvents obtained a pale yellow sticky solid. This wassuspended in 50 mL of water and basified with 1 N NaOH solution untilthe pH was 12. The basic layer was washed once with 25 mL of ethylacetate. After a back-extraction of the organic phase with 20 mL ofwater at pH=12, the combined basic phases were acidified with 1 N HCluntil pH=5 was reached. After standing overnight the precipitate wascollected and dried to afford2-chloro-4-(5-(cyclopropanesulfon-amido)pyridin-3-yl)benzoic acid (0.438g, 1.24 mmol, 35%) as an off-white solid. MS (ESI, pos. ion) m/z: 353,355 (M+1).

N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanecarboxamide

3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.50 g, 2.28mmol) and N,N-diisopropylethylamine (1.20 ml, 6.85 mmol), were combinedin dichloromethane (5 mL) to give a light yellow solution.Cyclobutanecarbonyl chloride (0.260 mL, 2.282 mmol) was added graduallyby syringe. The mixture was stirred for 2.5 h. The reaction was dilutedwith 70 mL of dichloromethane and then was washed twice with 20 mL ofwater. The organic layer was then washed with 20 mL of brine and driedover MgSO₄. Concentrating gave a white solid which was purified viacolumn chromatography on silica gel (Biotage 50 g column, gradientelution with 0-40% ethyl acetate/hexanes) to affordN-(4′-(4-(1-hydroxycyclopropanecarbonyl)piperazine-1-carbonyl)biphenyl-3-yl)oxetane-3-carboxamideas a waxy white solid. MS (ESI, pos. ion) m/z 302 (M+1).

1 N-(5-bromopyridin-3-yl)cyclopropanecarboxamide

5-Bromopyridin-3-amine (0.292 mL, 2.89 mmol) andN,N-diisopropylethylamine (0.757 mL, 4.33 mmol) were combined indichloromethane (15 mL) to give a light yellow solution.Cyclopropanecarbonyl chloride (0.263 mL, 2.89 mmol) was added graduallyby syringe. The reaction was stirred at rt for 1.5 h. The reaction wasdiluted with 50 mL of dichloromethane and washed with 25 mL of saturatedNaHCO₃. After extracting the aqueous layer with 20 mL of dichloromethanethe combined organic layers were washed with 20 mL NaHCO₃, 20 mL ofbrine, and dried over MgSO₄. The solvent was concentrated leaving abrown semi-solid. The residue was purified via column chromatography onsilica gel (Biotage 50 g column, gradient elution with 0-4%methanol/dichloromethane) to affordN-(5-bromopyridin-3-yl)cyclopropanecarboxamide (0.603 g, 2.50 mmol, 87%)as a light tan solid. MS (ESI, pos. ion) m/z: 241,243 (M+1).

N-(3-bromophenyl)ethanesulfonamide

3-Bromoaniline (0.158 mL, 1.453 mmol), and pyridine (0.118 mL, 1.453mmoles) were combined in water (10 mL) to give a tan solution andethanesulfonyl chloride (0.138 mL, 1.453 mmol) was added gradually bysyringe. After 1 h additional ethanesulfonyl chloride (0.138 ml, 1.453mmol) was added and the stirring was continued another 1 h. The reactionwas extracted with twice with 15 mL of ethyl acetate and the combinedorganic layers were washed with 10 mL of brine and dried over MgSO₄. Thesolvent was concentrated to afford a pale red oil. This material waspurified via column chromatography on silica gel (Biotage 25 g column,gradient elution with 0-30% ethyl acetate/hexanes) to affordN-(3-bromophenyl)ethanesulfonamide (0.345 g, 1.24 mmol, 85%) as acolorless viscous film that partially solidified on standing. MS (ESIneg. ion) m/z 262,264 (M−1).

(3′-aminobiphenyl-4-yl)(4-(1-hydroxycyclopropanecarbonyl)piperazin-1-yl)methanone

(4-(1-Hydroxycyclopropanecarbonyl)piperazin-1-yl)(3′-nitrobiphenyl-4-yl)methanone(0.263 g, 0.665 mmol, prepared according to General Method B) wassuspended in ethanol (6 mL) and water (2 mL). Iron powder (0.371 g, 6.65mmol) and ammonium chloride (8.89 mg, 0.166 mmol) were added and thesuspension was heated at 80° C. for 2 h. The suspension was diluted withmethanol and filtered through Celite. The filtrate was concentrated and50 mL of chloroform was added. The solution was washed with 30 mL ofsaturated NaHCO₃ and the aqueous phase was separated and washed with 20mL chloroform. The combined organic layers were washed with 20 mL ofbrine and dried over MgSO₄. The mixture was concentrated and the residuewas purified via column chromatography on silica gel (Biotage 25 gcolumn, gradient elution with 0-6% methanol/chloroform) to afford anamber film. This was taken up in dichloromethane and triturated withhexanes to afford(3′-aminobiphenyl-4-yl)(4-(1-hydroxycyclopropanecarbonyl)-piperazin-1-yl)methanone(0.152 g, 0.345 mmol, 52%) as a foamy solid. MS (ESI, pos. ion) m/z 366(M+1).

tert-butyl4-(2-chloro-4-(5-(cyclopropanesulfonamido)pyridin-3-yl)benzoyl)piperazine-1-carboxylate

tert-Butyl piperazine-1-carboxylate (0.139 g, 0.748 mmol),2-chloro-4-(5-(cyclopropanesulfonamido)-pyridin-3-yl)benzoic acid (0.240g, 0.680 mmol) and N,N-diisopropylethylamine (0.131 mL, 0.748 mmol) werecombined in DMF (5 mL), andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(0.387 g, 1.020 mmol) was added to give a brown solution. This wasstirred for 1 d.

The reaction was diluted with 30 mL of water and stirred. The mixturewas extracted with 60 mL dichloromethane and then with 15 mL ofdichloromethane. The combined organic layers were washed with 20 mL ofwater and 20 mL of brine, and concentrated. The residue was purified viacolumn chromatography on silica gel (Biotage 50 g column, gradientelution with 0-4% methanol/dichloromethane) to afford tert-butyl4-(2-chloro-4-(5-(cyclopropanesulfonamido)pyridin-3-yl)benzoyl)piperazine-1-carboxylate(0.252 g, 71% yield) as an amber glassy film. MS (ESI, pos. ion) m/z:521/523.

tert-butyl4-(2-chloro-4-(5-(cyclopropanecarboxamido)pyridin-3-yl)benzoyl)piperazine-1-carboxylate

tert-Butyl piperazine-1-carboxylate (0.137 g, 0.736 mmol),2-chloro-4-(5-(cyclopropanecarboxamido)-pyridin-3-yl)benzoic acid (0.212g, 0.669 mmol), and N,N-diisopropylethylamine (0.129 mL, 0.736 mmol)were combined in DMF (5 mL) followed byO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(0.381 mg, 1.004 mmol) to give a brown solution. This was stirred for 1d. Water (10 mL) was added and the reaction was stirred. The suspensionwas diluted with 60 mL of dichloromethane and 20 mL of water. Theaqueous phase was separated and extracted with 15 mL of dichloromethane.The combined organic layers were washed with 20 mL of water and 20 mL ofbrine, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The crude product was purified via column chromatographyon silica gel (Biotage 50 g column, gradient elution with 0-4%methanol/dichloromethane) to afford tert-butyl4-(2-chloro-4-(5-(cyclopropanecarboxamido)-pyridin-3-yl)benzoyl)piperazine-1-carboxylate(0.454 g, 140%) as an amber glass. MS (ESI, pos. ion) m/z: 485/487.

tert-butyl 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-carboxylate

Into a 100-mL round-bottom flask, was placed5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (800 mg, 3.77 mmol, 1.00equiv), Boc₂O (1.22 g, 5.59 mmol, 1.50 equiv), 4-dimethylaminopyridine(55 mg, 0.45 mmol, 0.12 equiv), TEA (756 mg, 7.47 mmol, 2.00 equiv) andtetrahydrofuran (20 mL). The resulting solution was stirred for 18 h at20° C. The resulting solution was diluted with 50 mL of H₂O, extractedwith 3×20 mL of ethyl acetate. The organic layers were combined, driedover anhydrous sodium sulfate and concentrated under vacuum. Thisresulted in 1.18 g (95%) of the title compound as a white solid. LC-MS(ES, m/z): 312, 314 [M+H]⁺

tert-butyl5-bromo-2-(((tert-butoxycarbonyl)oxy)methyl)-1H-benzo[d]imidazole-1-carboxylate

Into a 50-mL round-bottom flask, was placed(5-bromo-1H-1,3-benzodiazol-2-yl)methanol (600 mg, 2.64 mmol, 1.00equiv), dichloromethane (20 mL), Boc₂O (1 g, 4.58 mmol, 1.73 equiv), TEA(800 mg, 7.91 mmol, 2.99 equiv), 4-dimethylaminopyridine (32 mg, 0.26mmol, 0.10 equiv). The resulting solution was stirred for 4 h at 25° C.The mixture was diluted with 20 mL of dichloromethane, washed with 3*30mL of water and 30 mL of brine. The organic phase was dried overanhydrous sodium sulfate and concentrated under vacuum. This resulted in600 mg (crude) of the title compound as yellow oil. LC-MS (ES, m/z)429,427[M+H]⁺

tert-butyl (3-(3-bromophenyl)-1H-pyrazol-5-yl)carbamate

Into a 50-mL round-bottom flask, was placed a solution of3-(3-bromophenyl)-1H-pyrazol-5-amine (500 mg, 2.10 mmol, 1.00 equiv) indichloromethane (20 mL), (Boc)₂O (916 mg, 4.20 mmol, 2.00 equiv),4-dimethylaminopyridine (25.6 mg, 0.21 mmol, 0.10 equiv), TEA (636.5 mg,6.29 mmol, 3.00 equiv). The resulting solution was stirred for 1 h atroom temperature. The reaction mixture was then poured into 100 mL ofwater, extracted with 2×100 mL of dichloromethane. The organic layerswere combined, dried over anhydrous sodium sulfate and concentratedunder vacuum. This resulted in 710 mg (100%) of tert-butylN-[3-(3-bromophenyl)-1H-pyrazol-5-yl]carbamate as brown oil. LC-MS (ES,m/z): 338[M+H]⁺

tert-butyl 3-bromo-7-fluoro-1H-indazole-1-carboxylate

Into a 50-mL round-bottom flask, was placed 3-bromo-7-fluoro-1H-indazole(700 mg, 3.26 mmol, 1.00 equiv), dichloromethane (20 mL), Boc₂O (1.5 g,6.87 mmol, 2.11 equiv), TEA (1 g, 9.88 mmol, 3.04 equiv),4-dimethylaminopyridine (40 mg, 0.33 mmol, 0.10 equiv). The resultingsolution was stirred for 4 h at 25° C. The resulting mixture was pouredinto 50 ml of water, extracted and concentrated under vacuum. Thisresulted in 1 g (crude) of the title compound as red oil. LC-MS (ES,m/z): 315, 317[M+H]⁺

tert-butyl (5-bromobenzo[d]isoxazol-3-yl)carbamate

Into a 50-mL round-bottom flask, was placed5-bromo-1,2-benzoxazol-3-amine (1 g, 4.69 mmol, 1.00 equiv),dichloromethane (20 mL), Boc₂O (2.1 g, 9.62 mmol, 2.05 equiv),4-dimethylaminopyridine (57 mg, 0.47 mmol, 0.10 equiv), TEA (1.4 g,13.84 mmol, 2.95 equiv). The reaction mixture was stirred for 3 h at 25°C. The resulting mixture was washed with 30 ml of water, 3×30 mL ofbrine, dried over anhydrous sodium sulfate and concentrated undervacuum. This resulted in 650 mg (crude) of the title compound as yellowoil. LC-MS (ES, m/z): 313, 315[M+H]⁺

2-chloro-6-fluoroquinazoline

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed 2,4-dichloro-6-fluoroquinazoline (1g, 4.61 mmol, 1.00 equiv), brine (23 mL), dichloromethane (25 mL),ammonia hydrate (2 ml), Zn (0.9 g, 13.8 mmol, 3.0 equiv). The resultingmixture was stirred for overnight at 50° C. in an oil bath. The reactionmixture was cooled to room temperature and diluted with 50 mL of H₂O,extracted with 2×100 mL of dichloromethane. The organic layers werecombined and concentrated under vacuum. The residue was purified byCombi-Flash with the following conditions (IntelFlash-1):Column, silicagel; mobile phase, EA:PE=100% increasing to EA:PE=60% within 40 min;Detector, UV 254 nm. This resulted in 0.35 g (35%) of the title compoundas a yellow solid. LC-MS (ES, m/z) 183 [M+H]⁺

6-bromo-1-methyl-1H-indazol-3-ol

Into a 5-mL sealed tube, was placed methyl 4-bromo-2-fluorobenzoate (300mg, 1.29 mmol, 1.00 equiv), methylhydrazine (71.4 mg, 1.55 mmol, 1.20equiv), DMA (2 mL). The resulting solution was stirred overnight at 150°C. in a sand bath. After cooled to room temperature, the reactionmixture was diluted with 10 mL of ethyl acetate, washed with 3×10 mL ofH₂O and 1×20 mL of brine. The organic phase was concentrated undervacuum. This resulted in 225 mg (77%) of6-bromo-1-methyl-1H-indazol-3-ol as an off-white solid. LC-MS (ES, m/z):227, 229 [M+H]⁺

6-bromo-1-(methylsulfonyl)-1H-indole

To a solution of 6-bromoindole (2.94 g, 15 mmol, 1 eq.) in anhydrous DMF(45 mL) cooled in an ice-water bath was added NaH (0.72 g, 18 mmol, 1.2eq.) portionwise under N₂. The mixture was stirred for additional 20min. and MeSO₂Cl (1.4 mL, 18 mmol, 1.2 eq.) was then added dropwise. Thereaction mixture was allowed to warm to room temperature and stirred for1 hour before being quenched with ice and diluted with EtOAc. Theorganic layer was washed with water (2×) and brine (2×), dried overNa₂SO₄ and concentrated in vacuum. The crude residue was purified byflash chromatography (silica gel) eluting with EtOAc/hexanes (0˜20%) togive the title compound as a white solid (0.94 g, 23%).Enzymatic Assay for FASN Inhibitors

Assays were performed in a 384-well black plate to measure theinhibition of FASN activities by individual compounds herein disclosed.An aliquot of 250 nL of compound was incubated with 10 μL of 40 nM FASNenzyme in assay buffer (50 mM HEPES pH=7.3, 0.5 mM EDTA, 1 mM Ascorbate,100 mM NaCl and 0.04% TritonX-100) in each well at 25° C. for 60minutes. After the plate was centrifuged briefly, 10 μL of substrate mix(20 M Acetyl-CoA, 60 M Malonyl-CoA, and 100 M NADPH in assay buffer) wasadded to each well. The reaction was maintained at 25° C. for 90minutes. The reaction was then quenched by adding 10 μL of 90 μM7-Diethylamino-3-(4′-Maleimidylpheynyl)-4-Methylcoumarin in 50/50Ethanol/H₂O solution. The assay plate was incubated at 25° C. for 15minutes, and read on a plate reader with excitation and emissionwavelength at 360 nm and 530 nm, respectively. The IC50 of a givencompound was calculated by fitting the dose response curve with a fourparameter logistic equation.

Results

Table 2-1 lists the compounds having an IC 50<0.5 μM.

Table 2-2 lists the compounds having an IC 50≥0.5 μM and <5.0 μM.

Table 2-3 lists the compounds having an IC 50≥5.0 μM.

In addition, the Molecular Weight, Mass Ion Spectrometry Results, HPLCretention time, and the Method used to synthesize the compound are alsolisted.

TABLE 2-1 HPLC retention Mol. Mass Ion time IC50 (uM) < 0.5 WeightObserved (min) Method 5-[4-({4-[(1- 456.54 457.16 1.29 10hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1-(propan-2-yl)-1H-indole- 3-carbonitrile1-[(4-{[4-(4-chloro-3- 402.85 403.10 1.37 1fluorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(6-methoxy-4-methylquinolin-2- 445.51 446.16 1.16 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[3-methyl-4-(quinolin-6- 415.48 416.21 0.92 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1-methyl-1H-indol-2- 403.47 404.25 1.56 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(2-methoxyquinolin-6- 431.18 432.08 2.28 2yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-({4-[(4-{imidazo[1,2-a]pyridin-2- 390.44 391.19 0.61 3yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-{[4-({3-chloro-4-[1-(trifluoromethyl)-1H-indol- 491.89 492.03 1.3 105-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol1-[(4-{[5-(1-methyl-1H-indol-5-yl)pyrazin-2- 405.45 406.22 1.09 5yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1,3-benzothiazol-5-yl)-2- 441.93 442.11 1.14 5chlorophenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol3-[3-fluoro-4-({4-[(1- 435.45 436.13 0.96 5hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]quinolin-2-ol 5-[4-({4-[(1- 414.46 415.15 1.09 2hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-2-carbonitrile1-[(4-{[4-(5-chloro-1,3-benzoxazol-2- 425.87 426.13 1.31 4yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(2,4- 419.30 419.12 1.47, 1.68 5dichlorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(quinolin-3- 401.46 402.14 0.99 1yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol3-[4-({4-[(oxetan-2-yl)carbonyl]piperazin-1- 401.46 402.14 0.95 2yl}carbonyl)phenyl]quinoline 1-[(4-{[4-(1,3-benzoxazol-2- 391.42 392.161.14 4 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[2-chloro-4-(quinolin-3- 435.90 436.16 1.11 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1-methyl-1H-1,3-benzodiazol-5- 404.46 405.08 0.68 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1H-indazol-3- 390.44 391.12 0.98 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1-methyl-1H-indol-5- 403.47 404.12 1.26 2yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1-benzofuran-5- 390.16 391.01 2.43 2yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1H-1,3-benzodiazol-5- 390.44 391.20 0.6 2yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1,3-dimethyl-1H-indazol-5- 418.49 419.09 1.07 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(2,1,3-benzothiadiazol-4- 408.47 409.11 1.17 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(6-methoxyquinolin-2- 431.48 432.20 1.16 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-({4-[(2-phenyl-1,3-benzothiazol-6- 407.49 408.09 1.22 5yl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-[(4-{[4-(1,3-benzothiazol-5- 407.49 408.13 1.04 2yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[3-methyl-4-(quinolin-3- 415.48 416.21 1.07 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[2-fluoro-4-(quinolin-6- 419.45 420.19 0.91 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(6-fluoroquinolin-2- 419.45 420.16 1.24 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[2-chloro-4-(1-methyl-1H-indol-5- 437.92 438.15 1.32 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1H-1,3-benzodiazol-4- 390.44 391.14 0.7 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1,3-benzothiazol-5-yl)-3- 421.51 422.16 1.13 5methylphenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1,3-benzothiazol-6- 407.49 408.14 1 2yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(4- 384.86 385.13 1.35 1chlorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(6-chloro-1,3-benzoxazol-2- 425.87 426.11 1.33 4yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(4-chloro-2- 402.85 403.12 1.36 1fluorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1,3-benzothiazol-5-yl)-3- 441.93 442.12 1.16 5chlorophenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[2-fluoro-4-(7-fluoro-1H-indol-5- 425.43 426.04 1.16 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1,3-benzothiazol-2- 407.49 408.09 1.24 6yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(4-chloroquinolin-3- 435.90 436.11 1.19 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(isoquinolin-1- 401.46 402.20 0.9 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(5-chloro-1H-1,3-benzodiazol-2- 424.88 425.08 1.01 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1,3-benzoxazol-5- 391.42 392.16 0.97 2yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1,3-benzoxazol-4- 391.42 392.16 1.1 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[3-fluoro-4-(quinolin-6- 419.45 420.18 0.91 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(3,4- 419.30 419.03 1.45 2dichlorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[6-(1-methyl-1H-indol-5-yl)pyridin-3- 404.46 405.21 1.04 5yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(2,1,3-benzothiadiazol-5- 408.47 409.11 1.17 3yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[2-fluoro-4-(quinolin-3- 419.45 420.18 1.07 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol5-[4-({4-[(1- 432.47 433.15 0.81 3hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-2-carboxamide1-[(4-{[4-(2-methyl-2H-indazol-6- 404.46 405.08 0.94 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol3-[4-({4-[(1- 417.46 418.15 0.93 1hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,2-dihydroquinolin-2-one 1-[(4-{[4-(3-chloro-4-402.85 403.11 1.36 1 fluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-{[4-({4-[2-methoxy-4-(1H-pyrazol-1-446.50 447.23 1.19 5 yl)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol 1-[(4-{[2-chloro-4-(quinolin-6- 435.90436.14 0.96 5 yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2-methyl-2H-indazol-5- 404.46405.17 0.88 7 yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(5-chloro-2- 402.85 403.10 1.33 1fluorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol5-[4-({4-[(1- 414.46 415.17 0.97 1hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-3-carbonitrile5-[4-({4-[(oxetan-2-yl)carbonyl]piperazin-1- 389.45 389.18 1.03 2yl}carbonyl)phenyl]-1H-indole 5-[2-chloro-4-({4-[(1- 448.90 449.10 1.065 hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-3-carbonitrile 1-[(4-{[4-(quinolin-5-401.46 402.17 0.84 7 yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol N-{3-[4-({4-[(1- 443.52 444.17 0.93 11hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}methanesulfonamide1-[(4-{[5-(1-methyl-1H-indol-5-yl)pyridin-2- 404.46 405.28 1.1 5yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[2-fluoro-4-(2-methoxyquinolin-3- 449.47 450.17 1.39 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-({4-[(4-phenylphenyl)carbonyl]piperazin-1- 350.41 351.20 1.2 5yl}carbonyl)cyclopropan-1-ol 1-[(4-{[4-(7-fluoro-1H-indol-5- 407.44408.12 1.11 5 yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol1-[(4-{[2,3-difluoro-4-(6-methoxyquinolin-2- 467.46 468.16 1.28 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-olN-{3-[4-({4-[(1- 469.55 470.08 1.04 11hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclopropanesulfonamide1-[(4-{[3-methyl-4-(1-methyl-1H-indol-5- 417.50 418.25 1.3 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(3- 406.47 407.08 1.37 7cyclopropoxyphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2,5- 419.30 419.13 1.43 5dichlorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[3-chloro-4-(1-methyl-1H-indol-5- 437.92 438.18 1.33 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol5-[3-chloro-4-({4-[(1- 448.90 449.10 1.06 5hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-3-carbonitrile1-[(4-{[4-(2H-1,2,3-benzotriazol-5- 391.42 392.14 0.79 3yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(3-chloro-2- 414.88 415.15 1.34 5methoxyphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[2,3-difluoro-4-(quinolin-2- 437.44 438.15 1.27 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1H-indol-2- 389.45 390.12 1.24 2yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol3-[3-chloro-4-({4-[(1- 504.00 504.05 1.15 3hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-N-cyclopropylbenzene-1- sulfonamide1-[(4-{[3-chloro-4-(quinolin-6- 435.90 436.16 0.99 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(5-fluoro-1,3-benzoxazol-2- 409.41 410.14 1.18 4yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1-methyl-1H-indol-5-yl)-2- 471.47 472.22 1.39 5(trifluoromethyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1-methyl-1H-indazol-6- 404.46405.09 1.05 5 yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol N-cyclopropyl-3-[4-({4-[(1- 433.50 434.130.95 7 hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]benzamide 1-[(4-{[4-(4-chloro-2- 414.88 415.17 1.37 5methoxyphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1-methyl-1H-indazol-5- 404.46 405.11 1.01 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[2-fluoro-4-(6-fluoroquinolin-2- 437.44 438.16 1.32 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(isoquinolin-6- 401.46 402.02 1.48 1yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-{[4-({4-[3- 420.50 421.16 1.4 5(cyclopropylmethoxy)phenyl]phenyl}carbonyl)piper-azin-1-yl]carbonyl}cyclopropan-1-ol 2-[4-({4-[(1- 416.43 417.14 1.07 4hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,3-benzoxazole-5- carbonitrile1-({4-[(4-{imidazo[1,2-b]pyridazin-6- 391.42 392.10 0.69 7yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-({4-[(4-{1H-pyrrolo[3,2-b]pyridin-5- 390.44 391.14 0.58 3yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-[(4-{[3-fluoro-4-(quinolin-3- 419.45 420.20 1.08 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[2-fluoro-4-(6-methoxyquinolin-2- 449.47 450.15 1.25 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(2,3- 419.30 419.08 1.38 2dichlorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[2,3-difluoro-4-(6-fluoroquinolin-2- 455.43 456.14 1.33 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-olN-cyclopropyl-3-[4-({4-[(1- 469.55 470.13 1.05 11hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]benzene-1-sulfonamide1-({4-[(4-{furo[3,2-b]pyridin-5- 391.42 392.08 0.97 7yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-({4-[(4-{3-chloroimidazo[1,2-a]pyridin-2- 424.88 425.06 0.98 3yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-[(4-{[4-(1,3-benzothiazol-5-yl)-3- 425.48 426.12 1.1 5fluorophenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-olN-{3-[4-({4-[(1- 471.57 472.19 1.08 11hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}propane-2- sulfonamide6-[4-({4-[(oxetan-2-yl)carbonyl]piperazin-1- 401.17 402.02 1.46 2yl}carbonyl)phenyl]isoquinoline N-{3-[4-({4-[(1- 505.59 506.10 1.18 11hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}benzenesulfonamide 1-{[4-({4-[2-methoxy-5-464.43 465.17 1.43 5 (trifluoromethoxy)phenyl]phenyl}carbonyl)piper-azin-1-yl]carbonyl}cyclopropan-1-ol 1-[(4-{[4-(2-chloro-4- 402.85 403.171.33 5 fluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(3- 384.86 385.06 1.33 1chlorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(quinolin-3- 415.48 416.04 2.13 1yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclobutan-1-ol1-({4-[(2-chloro-4-{imidazo[1,2-a]pyridin-2- 424.88 425.11 0.71 3yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-[(4-{[4-(1H-indol-5- 389.17 390.06 2.11 2yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(isoquinolin-6- 415.48 416.04 1.61 1yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclobutan-1-ol1-[(4-{[2-fluoro-4-(1-methyl-1H-indol-5- 421.46 422.22 1.29 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(6-fluoro-1,3-benzoxazol-2- 409.41 410.14 1.2 4yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-olN-{3-[4-({4-[(1- 433.50 434.13 1.06 5hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}cyclo- propanecarboxamide1-({4-[(4-{pyrazolo[1,5-a]pyridin-2- 390.44 391.15 0.95 3yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-[(4-{[3-chloro-4-(quinolin-3- 435.90 436.15 1.14 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(quinolin-2- 401.46 402.16 1.14 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1H-indol-4- 389.45 390.18 1.06 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol6-[4-({4-[(1- 417.46 418.13 0.76 3hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,2-dihydroquinolin-2-one 2-[4-({4-[(1- 416.43417.15 1.06 4 hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,3-benzoxazole-6- carbonitrile1-{[4-{3-chloro-4-[1-(propan-2-yl)-1H-indol-5- 465.97 466.05 1.5 10yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol1-[(4-{[4-(6-methoxynaphthalen-2- 430.50 431.12 1.36 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-olN-(3-{4-[4-(1- 461.23 462.15 1.23 30hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclopentanecarboxamide 1-(4-{4-[4-(1H-pyrazol-4-416.18 417.05 0.93 31 yl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol 1-{4-[4-(1,2,3,4-tetrahydroisoquinolin-2-405.21 406.15 1.25 20 yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(1,3-dimethyl-1H-indazol-5-yl)-2- 435.21 436.27 0.88 14fluorobenzoyl]piperazine-1- carbonyl}cyclopropan-1-amine1-(4-{4-[4-(1-methyl-1H-pyrazol-4- 430.20 431.06 1.03 31yl)phenyl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol1-[(2S)-4-[2-fluoro-4-(1-methyl-1H-1,3- 436.19 437.20 0.74 27benzodiazol-5-yl)benzoyl]-2-methylpiperazine-1-carbonyl]cyclopropan-1-ol 1-{4-[3-chloro-4-(1-methyl-1H-indazol-6-438.15 439.11 1.11 13 yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[2-fluoro-4-(1-methyl-1H-1,3-benzodiazol-5- 422.18 423.17 0.70 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[3-chloro-4-(1-methyl-1H-1,3-benzodiazol-5- 438.15 439.09 0.74 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-[4-(4-{pyrazolo[1,5-a]pyridin-6- 390.17 391.11 0.97 13yl}benzoyl)piperazine-1-carbonyl]cyclopropan-1-ol1-{4-[4-(4-fluoro-2,3-dihydro-1H-indol-1- 409.18 410.23 1.34 19yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(3-methyl-1H-indazol-6- 404.18 405.15 0.95 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[2-fluoro-4-(3-methyl-1H-indazol-7- 422.18 423.16 1.11 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-[(2S)-2-methyl-4-[4-(1-methyl-1H-indazol-6- 418.20 419.25 1.06 3yl)benzoyl]piperazine-1-carbonyl]cyclopropan-1-ol1-{4-[3-chloro-4-(2-methyl-2H-indazol-6- 438.15 439.10 1.00 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol3,3,3-trifluoro-N-(3-{4-[4-(1- 525.15 526.06 1.20 11hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)propane-1-sulfonamide1-{4-[2-fluoro-4-(1-methyl-1H-indazol-6- 422.18 423.11 1.06 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{3,3-dimethyl-4-[4-(1-methyl-1H-1,3- 432.22 433.20 0.75 24benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol1-{4-[2,6-difluoro-4-(1-methyl-1H-1,3- 440.17 441.17 0.75 32benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol1-{4-[2-fluoro-4-(1-methyl-1H-indazol-6- 435.21 436.27 0.88 14yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1- amine1-{4-[3-chloro-4-(6-chloro-1,3-benzoxazol-2- 459.08 460.02 1.40 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(1,3-dimethyl-1H-indazol-5-yl)-2- 436.19 437.16 1.08 13fluorobenzoyl]piperazine-1-carbonyl}cyclopropan-1-ol N-(3-{4-[4-(1-483.18 484.16 1.07 33 hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclobutanesulfonamide1-{4-[4-(2,3-dihydro-1H-indol-1- 391.19 392.18 1.24 19yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[3-chloro-4-(1,3-dimethyl-1H-indazol-5- 452.16 453.10 1.13 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-[(2S)-2-methyl-4-[4-(1-methyl-1H-1,3- 418.20 419.26 0.70 23benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol1-{4-[2,6-difluoro-4-(2-methyl-2H-indazol-6- 440.17 441.16 0.97 32yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-(4-{4-[3-(5-amino-1,2-oxazol-3-yl)phenyl]-2- 450.17 451.12 1.02 13fluorobenzoyl}piperazine-1-carbonyl)cyclopropan-1-ol1-[(2S)-2-methyl-4-[4-(2-methyl-2H-indazol-6- 418.20 419.23 0.95 3yl)benzoyl]piperazine-1-carbonyl]cyclopropan-1-ol1-cyclobutyl-N-(3-{4-[4-(1- 497.20 498.10 1.21 34hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)methanesulfonamide1-{4-[2-fluoro-4-(7-fluoro-1H-indazol-3- 426.15 427.12 1.07 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-[(2S)-4-[4-(6-chloro-1,3-benzoxazol-2- 439.13 440.18 1.39 23yl)benzoyl]-2-methylpiperazine-1- carbonyl]cyclopropan-1-ol1-{4-[4-(1H-indol-1-yl)benzoyl]piperazine-1- 389.17 390.06 1.30 18carbonyl}cyclopropan-1-ol 1-{4-[4-(7-fluoro-1H-indazol-3- 408.16 409.080.99 3 yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-2- 423.20 424.20 1.28 19yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[2-fluoro-4-(2-methyl-2H-indazol-6- 422.18 423.14 0.94 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(3-amino-1H-indazol-6- 405.18 406.17 0.71 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(3-amino-1,2-benzoxazol-5- 406.16 407.11 0.86 3yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(1,3-dimethyl-1H-indazol-5-yl)-2- 449.22 450.29 0.89 14fluorobenzoyl]piperazine-1-carbonyl}cyclobutan- 1-amine1-{4-[2-fluoro-4-(3-methyl-1H-indazol-6- 422.18 423.24 1.03 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol ethyl N-(3-{4-[4-(1-437.20 438.13 1.12 11 hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)carbamate1-{4-[4-(5-chloro-2-methyl-1H-1,3-benzodiazol-7- 438.15 439.09 0.83 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-[4-(4-{1H,2H,3H,4H,9H-pyrido[3,4-b]indol-2- 444.22 445.17 1.26 19yl}benzoyl)piperazine-1-carbonyl]cyclopropan-1-ol1-[(2R,6S)-2,6-dimethyl-4-[4-(1-methyl-1H-1,3- 432.22 433.20 0.73 23benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol1-[4-(2-chloro-4-{3-chloroimidazo[1,2-a]pyridin- 458.09 459.06 1.07 132-yl}benzoyl)piperazine-1-carbonyl]cyclopropan-1-ol1-{4-[4-(4-chloro-2-fluorophenyl)benzoyl]-3,3- 430.15 431.14 1.47 24dimethylpiperazine-1-carbonyl}cyclopropan-1-ol1-{4-[2-chloro-4-(1-methyl-1H-indazol-6- 438.15 439.10 1.10 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-[(2S)-4-[4-(4-chloro-2-fluorophenyl)benzoyl]-2- 416.13 417.14 1.40 23methylpiperazine-1-carbonyl]cyclopropan-1-ol1-[(2S)-4-[4-(1,3-dimethyl-1H-indazol-5- 432.22 433.27 1.10 3yl)benzoyl]-2-methylpiperazine-1- carbonyl]cyclopropan-1-ol1-(4-{4-[3-(5-amino-1,2-oxazol-3- 432.18 433.23 0.97 22yl)phenyl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol 2-(3-{4-[4-(1-389.17 390.12 1.06 13 hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)acetonitrile N-(3-{4-[4-(1-hydroxycyclopropanecarbonyl)piperazine-1- 497.20 498.16 1.14 33carbonyl]phenyl}phenyl)cyclopentanesulfonamide1-[(3S)-3-methyl-4-[4-(1-methyl-1H-1,3- 418.20 419.21 0.67 23benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol1-cyclopropyl-N-(3-{4-[4-(1- 483.18 484.05 1.13 34hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)methanesulfonamide1-{4-[3-chloro-4-(6-fluoro-1,3-benzoxazol-2- 443.10 444.08 1.25 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[2-chloro-4-(2-methyl-2H-indazol-6- 438.15 439.09 0.98 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[2,6-difluoro-4-(1-methyl-1H-indazol-6- 440.17 441.14 1.10 32yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-[(3R)-3-methyl-4-[4-(1-methyl-1H-1,3- 418.20 419.25 0.69 23benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-olN-(6-{4-[4-(1- 474.19 475.15 1.01 29hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-1,2-benzoxazol-3- yl)cyclopropanecarboxamide1-[(3R,5S)-3,5-dimethyl-4-[4-(1-methyl-1H-1,3- 432.51 433.16 0.74 23benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-olpropan-2-yl N-(3-{4-[4-(1- 451.21 452.16 1.24 11hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)carbamate 1-{4-[4-(3-amino-1H-indazol-5- 405.18406.17 0.73 13 yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-[(2R)-2-methyl-4-[4-(1-methyl-1H-1,3- 418.20 419.25 0.69 23benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol3,3-difluoro-N-(3-{4-[4-(1- 483.20 484.14 1.19 30hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclobutane-1- carboxamide1-[(2S,6R)-4-[4-(6-fluoro-1,3-benzoxazol-2- 437.18 438.13 1.28 4yl)benzoyl]-2,6-dimethylpiperazine-1- carbonyl]cyclopropan-1-ol1-(4-{4-[1-(2-hydroxyethyl)-1H-1,3-benzodiazol- 434.20 435.19 0.59 216-yl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol1-{4-[4-(1H-1,3-benzodiazol-4-yl)-2- 424.13 425.04 0.79 5chlorobenzoyl]piperazine-1- carbonyl}cyclopropan-1-ol1-{4-[4-(5-fluoro-2,3-dihydro-1H-indol-1- 409.18 410.17 1.28 19yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-[4-(4-{3-chloroimidazo[1,2-a]pyridin-2-yl}-2- 442.12 443.12 1.00 13fluorobenzoyl)piperazine-1- carbonyl]cyclopropan-1-ol1-{4-[4-(4-chloro-2-fluorophenyl)-2- 420.11 421.01 1.39 15fluorobenzoyl]piperazine-1- carbonyl}cyclopropan-1-ol1-{4-[3-chloro-4-(4-chloro-2- 436.08 437.04 1.44 15fluorophenyl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol1-{4-[2-chloro-4-(6-chloro-1,3-benzoxazol-2- 459.08 460.03 1.43 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(5-fluoro-2,3-dihydro-1H-isoindol-2- 409.18 410.23 1.31 19yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(3-methyl-1H-indazol-4- 404.18 405.15 0.90 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(6-methoxy-1,3-benzoxazol-2- 421.16 422.04 1.13 4yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(3-methyl-1H-indazol-7- 404.18 405.13 1.05 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-[(2R)-4-[4-(4-chloro-2-fluorophenyl)benzoyl]-2- 416.13 417.14 1.40 23methylpiperazine-1-carbonyl]cyclopropan-1-ol 1-(3-{4-[4-(1- 429.21430.20 1.23 13 hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclobutane-1-carbonitrile1-{4-[2-fluoro-4-(6-fluoro-1,3-benzoxazol-2- 427.13 428.09 1.22 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-[4-(4-{1H,2H,3H,4H,5H-pyrido[4,3-b]indol-2- 444.22 445.16 1.20 19yl}benzoyl)piperazine-1-carbonyl]cyclopropan-1-ol1-{4-[4-(2-methyl-1H-indol-1- 403.19 404.15 1.32 18yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-[(2S)-2-methyl-4-[4-(1-methyl-1H-1,3- 417.22 418.23 0.54 28benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-amine1-{4-[3-fluoro-4-(1-methyl-1H-1,3-benzodiazol-5- 422.18 423.14 0.68 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[2-fluoro-4-(1-methyl-1H-1,3-benzodiazol-5- 435.21 436.27 0.57 14yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1- amine1-{4-[3-fluoro-4-(1-methyl-1H-indazol-6- 422.18 423.09 1.05 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-[(2S)-4-[4-(6-fluoro-1,3-benzoxazol-2- 423.16 424.18 1.21 4yl)benzoyl]-2-methylpiperazine-1- carbonyl]cyclopropan-1-ol1-{4-[4-(4-fluoro-2,3-dihydro-1H-isoindol-2- 409.18 410.21 1.30 19yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol 1-(4-{3-chloro-4-[3-488.12 489.07 1.10 13 (cyclopropanesulfonyl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol 1-{4-[4-(7-fluoro-2,3-dihydro-1H-indol-1-409.18 410.23 1.28 19 yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(3-cyclopropyl-1H-indazol-6- 430.20 431.15 1.09 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(6-fluoro-1,3-benzoxazol-2-yl)benzoyl]- 437.18 438.19 1.28 243,3-dimethylpiperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(3-methyl-1H-indazol-1- 404.18 405.11 1.14 18yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[2-fluoro-4-(3-methyl-1H-indazol-7- 421.19 422.20 0.91 14yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1- amine1-{4-[4-(1-methanesulfonyl-1H-indol-6- 467.15 468.03 1.20 3yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(1-methyl-1H-1,3-benzodiazol-5- 403.20 404.16 0.81 14yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1- amine1-{4-[4-(2-methyl-2,3-dihydro-1H-indol-1- 405.21 406.24 1.37 19yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(5-fluoro-1H-1,2,3-benzotriazol-6- 409.16 410.10 0.79 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[3-chloro-4-(5-chloro-2- 436.08 436.98 1.40 13fluorophenyl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol1-[(2S,6R)-4-[4-(4-chloro-2- 430.15 431.18 1.48 23fluorophenyl)benzoyl]-2,6-dimethylpiperazine-1-carbonyl]cyclopropan-1-ol N-(3-{4-[4-(1- 513.19 514.05 0.98 34hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)oxane-4-sulfonamide1-{4-[4-(1-methyl-1H-indazol-6- 403.20 404.15 0.79 14yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1- amine1-{4-[4-(7-methoxy-1,2,3,4- 435.22 436.21 1.26 19tetrahydroisoquinolin-2-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol 1-(3-{3-fluoro-4-[4-(1- 433.18 434.16 1.22 13hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclopropane-1-carbonitrile1-{4-[2-fluoro-4-(2-methyl-1H-indol-1- 421.18 422.12 1.41 18yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(1H-1,3-benzodiazol-1- 390.17 391.14 0.81 18yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol 1-(3-{4-[4-(1- 415.19416.18 1.14 13 hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclopropane-1-carbonitrile1-{4-[2-fluoro-4-(3-methyl-1H-indazol-1- 422.18 423.09 1.25 18yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[2-fluoro-4-(1-methyl-1H-indazol-6- 421.19 422.20 0.86 14yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1- amine 2-{4-[4-(1- 430.20431.19 1.15 19 hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-1,2,3,4-tetrahydroisoquinoline- 7-carbonitrile1-(4-{4-[1-(2-hydroxyethyl)-1H-1,3-benzodiazol- 434.20 435.23 0.59 215-yl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol1-[(2R)-4-[4-(6-fluoro-1,3-benzoxazol-2- 423.16 424.18 1.20 4yl)benzoyl]-2-methylpiperazine-1- carbonyl]cyclopropan-1-ol1-{4-[4-(1H-indazol-1-yl)benzoyl]piperazine-1- 390.17 391.10 1.08 18carbonyl}cyclopropan-1-ol 1-{4-[2-chloro-4-(5-chloro-2- 436.08 437.001.40 13 fluorophenyl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol1-{4-[4-(1,3-dimethyl-1H-indazol-5-yl)-3- 436.19 437.12 1.07 13fluorobenzoyl]piperazine-1- carbonyl}cyclopropan-1-ol1-{4-[4-(4-chloro-2-fluorophenyl)benzoyl]-4,7- 428.13 429.15 1.48 24diazaspiro[2.5]octane-7-carbonyl}cyclopropan-1-ol1-{4-[2-fluoro-4-(7-fluoro-1H-indazol-3- 425.17 426.10 0.87 14yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1- amine 6-{1-[4-(1- 432.22433.17 1.25 36 hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]piperidin-4-yl}naphthalene-2- carbonitrile 1-(3-{4-[4-(1-434.20 435.24 0.91 13 hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)imidazolidin-2-one1-{4-[2,6-difluoro-4-(2-methyl-2H-indazol-6- 439.18 440.19 0.80 14yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1- amine1,3-dimethyl-5-{4-[4-(oxetane-2- 418.20 419.16 1.00 13carbonyl)piperazine-1-carbonyl]phenyl}-1H- indazole1-{4-[2-fluoro-4-(2-methyl-2H-indazol-6- 421.19 422.26 0.78 14yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1- amine1-(4-{4-[3-(5-amino-1H-1,2,4-triazol-3- 432.19 433.14 0.75 13yl)phenyl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol1-{4-[4-(1-methyl-1H-1,3-benzodiazol-5- 430.20 431.21 0.74 24yl)benzoyl]-4,7-diazaspiro[2.5]octane-7- carbonyl}cyclopropan-1-ol1-{4-[4-(2-methyl-1H-indol-3- 403.19 404.28 1.15 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(2-methyl-1H-1,3-benzodiazol-5- 404.18 405.14 0.59 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(6-fluoro-1,3-benzoxazol-2-yl)benzoyl]- 435.16 436.17 1.28 244,7-diazaspiro[2.5]octane-7- carbonyl}cyclopropan-1-ol1-{4-[4-(6-fluoro-1-methyl-1H-1,2,3-benzotriazol- 423.17 424.12 0.92 135-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(1-methyl-1H-1,3-benzodiazol-5- 418.20 419.04 0.73 1yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1-ol 6-chloro-4-{4-[4-(1-440.13 441.07 0.92 13 hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-2,3-dihydro-1H-1,3- benzodiazol-2-one1-(4-{4-[2-(hydroxymethyl)-1H-1,3-benzodiazol- 420.18 421.13 0.57 135-yl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol 5-{4-[4-(1- 405.18406.18 0.70 14 aminocyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-1,2-benzoxazol-3-amine1-{4-[4-(2-cyclopropyl-2H-indazol-5- 430.20 431.12 1.04 7yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[2-fluoro-4-(5,6,7,8-tetrahydro-1,7- 424.19 425.15 0.84 19naphthyridin-7-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol1-{4-[4-(3-methyl-1,2,3,4-tetrahydroisoquinolin- 419.22 420.21 1.38 192-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(2,3-dihydro-1H-isoindol-2- 391.19 392.18 1.22 19yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-[(3R)-4-[4-(4-chloro-2-fluorophenyl)benzoyl]-3- 416.13 417.14 1.40 23methylpiperazine-1-carbonyl]cyclopropan-1-ol1-[4-(4-{3-methyl-1H-pyrazolo[3,4-b]pyridin-5- 405.18 406.13 0.76 13yl)benzoyl)piperazine-1-carbonyl]cyclopropan-1-ol1-{4-[4-(3-methyl-1H-indazol-6- 403.20 404.26 0.80 14yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1- amine1-{4-[2-fluoro-4-(1-methyl-1H-1,3-benzodiazol-5- 421.19 422.20 0.54 14yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1- amine 6-{4-[4-(1- 420.18421.11 0.78 13 hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-1-methyl-1H-indazol-3-ol1-{4-[4-(1,2,3,4-tetrahydroquinolin-1- 405.21 406.14 1.33 20yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(3-methyl-1H-indazol-7- 403.20 404.20 0.88 14yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1- amine1-[4-(4-{4H,5H,6H,7H-thieno[3,2-c]pyridin-5- 411.16 412.15 1.23 19yl}benzoyl)piperazine-1-carbonyl]cyclopropan-1-ol1-{4-[4-(1-methyl-1H-indazol-6- 417.22 418.29 0.84 14yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1- amine1-(4-{4-[3-(2-amino-1,3-thiazol-4- 448.16 449.14 0.97 13yl)phenyl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol1-{4-[4-(1,3-dimethyl-1H-indazol-5- 431.23 432.31 0.86 14yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1- amine1-(4-{4-[3-(cyclopropanesulfonyl)phenyl]-2- 472.15 473.13 1.05 13fluorobenzoyl}piperazine-1- carbonyl)cyclopropan-1-ol1-{4-[4-(6-fluoroquinazolin-2- 420.16 421.10 1.13 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol N-(5-{4-[4-(1- 474.19475.15 1.00 29 hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-1,2-benzoxazol-3- yl)cyclopropanecarboxamide4-{4-[4-(1- 419.18 420.13 0.94 13hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-1-methyl-2,3-dihydro-1H-indol- 2-one1-[(3R)-4-[4-(6-fluoro-1,3-benzoxazol-2- 423.16 424.18 1.20 4yl)benzoyl]-3-methylpiperazine-1- carbonyl]cyclopropan-1-ol1-{4-[4-(2-methyl-1H-1,3-benzodiazol-1- 404.18 405.17 0.71 17yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol 1-{4-[4-(5-chloro-2-401.13 402.09 1.06 14 fluorophenyl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine 1-{4-[3-fluoro-4-(2-methyl-2H-indazol-6-422.18 423.10 0.94 13 yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol3-{4-[4-(1- 407.18 408.18 0.80 13hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-N-methylbenzamide 1-(4-{4-[3-(5-amino-1H-pyrazol-3-431.20 432.18 0.79 25 yl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol 1-[(2S)-2-methyl-4-[4-(5,6,7,8-tetrahydro-1,7-420.22 421.09 1.02 19 naphthyridin-7-yl)benzoyl]piperazine-1-carbonyl]cyclopropan-1-ol1-[(3S)-4-[4-(4-chloro-2-fluorophenyl)benzoyl]-3- 416.13 417.14 1.40 23methylpiperazine-1-carbonyl]cyclopropan-1-ol 2-(3-{4-[4-(1- 437.20438.19 0.86 13 hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenoxy)-N-methylacetamide1-{4-[4-(1-cyclopropyl-1H-indazol-5- 430.20 431.12 1.15 7yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-methyl-5-{4-[4-(oxetane-2-carbonyl)piperazine- 404.18 405.13 0.60 131-carbonyl]phenyl}-1H-1,3-benzodiazole(1-{4-[4-(1-methyl-1H-1,3-benzodiazol-5- 418.20 419.19 0.60 1yl)benzoyl]piperazine-1- carbonyl}cyclopropyl)methanol1-{4-[4-(1-methyl-1H-1,3-benzodiazol-5- 417.22 418.23 0.53 14yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1- amine1-{4-(3-chloro-4-{3-chloroimidazo[1,2-a]pyridin- 458.09 459.08 1.00 132-yl}benzoyl)piperazine-1-carbonyl]cyclopropan-1-ol1-[(2R)-2-(hydroxymethyl)-4-[4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- 434.20 435.25 0.60 23carbonyl]cyclopropan-1-ol 1-{4-[4-(2,3,4,5-tetrahydro-1H-3-benzazepin-3-419.22 420.28 1.35 19 yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-[(2S,6R)-4-[4-(6-fluoro-1,3-benzoxazol-2- 436.19 437.23 1.06 28yl)benzoyl]-2,6-dimethylpiperazine-1- carbonyl]cyclopropan-1-amine1-[(2S)-4-[4-(6-fluoro-1,3-benzoxazol-2- 422.18 423.16 0.99 28yl)benzoyl]-2-methylpiperazine-1- carbonyl]cyclopropan-1-amine1-(4-{4-[3-(5-methyl-1,3,4-thiadiazol-2- 448.16 449.14 1.01 13yl)phenyl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol1-{4-[4-(3-methyl-2H-indazol-2- 404.18 405.18 1.18 26yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol 2-(3-{4-[4-(1- 417.21418.23 1.23 1 hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)-2-methylpropanenitrile 1-[(2S)-4-{4-[3- 468.17469.23 1.08 3 (cyclopropanesulfonyl)phenyl]benzoyl}-2-methylpiperazine-1-carbonyl]cyclopropan-1-ol 1-(3-{4-[4-(1- 433.20434.18 0.95 13 hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)pyrrolidin-2-one 3-(3-{4-[4-(1- 449.19 450.190.82 14 aminocyclopropanecarbonyl)piperazine-1-carbonyl]-3-fluorophenyl}phenyl)-1,2-oxazol-5- amine 6-{4-[4-(1- 408.18409.14 0.80 3 hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-N-methylpyridine-2- carboxamide1-[(3S)-4-[4-(6-fluoro-1,3-benzoxazol-2- 423.16 424.18 1.20 4yl)benzoyl]-3-methylpiperazine-1- carbonyl]cyclopropan-1-ol4-(3-{4-[4-(1- 459.22 460.23 1.13 13hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)oxane-4-carbonitrile1-(4-{4-[3-(5-methyl-1,2,4-oxadiazol-3- 432.18 433.12 1.13 13yl)phenyl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol 5-(3-{4-[4-(1-462.19 463.22 0.81 13 hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)-5-methylimidazolidine- 2,4-dione1-{4-[2-fluoro-4-(2-methyl-1H-indol-1- 420.20 421.16 1.15 35yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1- amine1-{4-[4-(3-amino-1,2-benzoxazol-6- 406.16 407.16 0.91 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[2-fluoro-4-(2-methyl-2H-indazol-6- 435.21 436.27 0.80 14yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1- amine 2-(3-{4-[4-(1-469.17 470.13 0.98 13 hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)-1λ⁶,2-thiazolidine-1,1- dione1-{4-[4-(6-chloro-1,3-benzoxazol-2-yl)-3- 443.10 444.05 1.30 13fluorobenzoyl]piperazine-1- carbonyl}cyclopropan-1-ol1-{4-[4-(2,3,4,5-tetrahydro-1H-2-benzazepin-2- 419.22 420.26 1.29 19yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-[4-(4-{3-chloroimidazo[1,2-a]pyridin-2-yl}-3- 442.12 443.07 0.98 13fluorobenzoyl)piperazine-1- carbonyl]cyclopropan-1-ol 1-(3-{4-[4-(1-414.21 415.16 0.97 14 aminocyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclopropane-1- carbonitrile1-{4-[3-fluoro-4-(6-fluoro-1,3-benzoxazol-2- 427.13 428.08 1.17 13yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-{4-[4-(2-methyl-2H-1,2,3-benzotriazol-5- 405.18 406.13 0.95 16yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol1-[(3S)-3-methyl-4-[4-(1-methyl-1H-1,3- 417.22 418.23 0.54 28benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-amine

TABLE 2-2 HPLC Mol. Mass Ion retention IC50 (uM) ≥0.5 and <5.0 WeightObserved time (min) Method 1-[(4-{[4-(2-fluoro-3- 398.43 399.20 1.19 5methoxyphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl}cyclopropan-1-ol1-{[4-({4-[2-fluoro-3- 452.40 453.16 1.43 5(trifluoromethoxy)phenyl]phenyl}carbonyl)-piperazin-1-yl]carbonyl}cyclopropan-1-ol1-({4-[(4-{6-chloroimidazo[1,2-a]pyridin-3- 424.88 425.04 0.75 7yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-({4-[(4-{furo[3,2-c]pyridin-4- 391.42 392.15 0.77 7yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-[(4-{[4-methyl-2-(quinolin-3-yl)-1,3-thiazol-5- 422.50 423.13 1.01 5yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-({4-[(4-{imidazo[1,2-a]pyrazin-6- 391.42 392.16 0.69 7yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol4-fluoro-3-[4-({4-[(1- 453.51 454.24 1.28 5hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-N-(propan-2-yl)benzamide 1-{[(3S)-4-{[4-(4-chloro-2-432.87 433.13 1.28 1 fluorophenyl)phenyl]carbonyl}-3-(hydroxymethyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol1-{[4-({4-[1-(trifluoromethyl)-1H-indol-5- 457.45 458.12 1.22 10yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol1-{[4-({4-[2-(trifluoromethyl)imidazo[1,2- 458.43 459.14 1.09 7a]pyridin-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol1-({4-[(4-{imidazo[1,2-a]pyrimidin-7- 391.42 392.16 0.55 7yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-[(4-{[2-methoxy-4-(quinolin-6- 431.48 432.20 0.86 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(5-methoxy-1H-1,3-benzodiazol-2- 420.46 421.18 0.75 7yl)phenyl}carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(4-chloro-1H-1,3-benzodiazol-2- 424.88 425.11 1 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[6-(2-methoxyquinolin-6-yl)pyridin-3- 432.47 433.17 1.16 5yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[5-(2-methoxyquinolin-6-yl)pyridin-2- yl]carbonyl}piperazin-1-432.47 433.17 1.17 5 yl)carbonyl]cyclopropan-1-ol1-[(4-{[2-(4-fluorophenyl)-1,3-benzothiazol-6- 425.48 426.07 1.26 5yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-{(4-{[4-(2-fluoro-5- 382.43 383.21 1.54 5methylphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1,3-benzothiazol-5-yl)-2- 437.51 438.17 1.06 5methoxyphenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-methyl-2-(1-methyl-1H-indol-5-yl)-1,3- 424.52 425.16 1.13 5thiazol-5-yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol6-[4-({4-[(1-hydroxycyclopropyl)- 407.42 408.14 0.84 7carbonyl]piperazin-1-yl}carbonyl)phenyl}-2,3-dihydro-1,3-benzoxazol-2-one1-[(4-{[5-(4-chloro-2-fluorophenyl)pyridin-2- 403.84 404.16 1.23 1yl{carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1H-1,3-benzodiazol-2- 390.44 391.14 0.73 3yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-{[4-({4-[2-chloro-5- 452.85 453.12 1.47 5(trifluoromethyl)phenyl]phenyl}carbonyl)piperazin--1-yl]carbonyl}cyclopropan-1-ol 1-[(4-{[5-(quinolin-6-yl)pyrazin-2-403.43 404.19 0.79 5 yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[6-(quinolin-6-yl)pyridin-3- 402.45403.17 0.73 5 yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-{[4-({4-[2-fluoro-3- 436.40 437.19 1.38 5(trifluoromethyl)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol 1-[(4-{[4-(quinolin-6-yl)-2- 469.46470.19 1.06 5 (trifluoromethyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-{[4-({4-[3-fluoro-5- 436.40 437.17 1.43 5(trifluoromethyl)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol 1-[(4-{[4-(5-fluoro-1H-1,3-benzodiazol-2-408.43 409.09 0.86 5 yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 4-fluoro-3-[4-({4-[(1- 425.45 426.19 1.1 5hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-N-methylbenzamide1-[(4-{[4-(3-methyl-1,2-benzoxazol-6- 405.45 406.17 1.01 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol5-[4-({4-[(1- 407.42 408.15 0.91 7hydroxycyclopropyl)carbonyl]piperazin-1-yl}car-bonyl)phenyl]-2,3-dihydro-1,3-benzoxazol-2-one1-({4-[(4-{[1,2,4]triazolo[4,3-b]pyridazin-6- 392.41 393.13 0.65 7yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-{[4-({4-[7-(trifluoromethyl)quinolin-4- 469.46 470.09 1.28 7yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol1-{[4-({4-[4-chloro-2- 452.85 453.15 1.5 5(trifluoromethyl)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol 1-{[4-({4-[1-(propan-2-yl)-1H-indazol-5-432.51 433.24 1.23 3 yl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol 1-[(4-{[5-(quinolin-3-yl)pyrazin-2- 403.43404.22 0.92 5 yl]carbonyl}piperazin-1- yl)carbonyl}cyclopropan-1-ol1-[(4-{[3-methoxy-4-(quinolin-6- 431.48 432.20 0.86 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(5,6-difluoro-1H-1,3-benzodiazol-2- 426.42 427.15 0.99 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1-methyl-1H-1,3-benzodiazol-2- 404.46 405.11 0.73 3yl)phenyl]carbonyl}piperazin-1- yl)carbonyl}cyclopropan-1-ol1-[(4-{[4-(2-fluoro-3- 382.43 383.22 1.54 5methylphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl}cyclopropan-1-ol1-({4-[(4-{6-methoxyimidazo[1,2-a]pyridin-2- 420.46 421.19 0.69 3yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-[(4-{[4-(2-fluoro-4- 398.43 399.20 1.45 5methoxyphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[5-(quinolin-6-yl)pyrimidin-2- 403.43 404.21 0.7 5yl]carbonyl}piperazin-1- yl)carbonyl}cyclopropan-1-ol1-({4-[(4-{imidazo[1,2-a]pyridin-6- 390.44 391.21 0.55 5yl}phenyl)carbonyl}piperazin-1- yl}carbonyl)cyclopropan-1-ol1-({4-[(4-phenylphenyl)carbonyl]piperazin-1- 364.44 365.17 1.29 1yl}carbonyl)cyclobutan-1-ol 1-{[4-({4-[4-fluoro-2- 436.40 437.20 1.38 5(trifluoromethyl)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol 1-[(4-{[4-(3-fluoro-4- 382.43 383.22 1.555 methylphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl}cyclopropan-1-ol1-[(4-{[4-(2,1,3-benzoxadiazol-5- 392.41 393.16 1.17 3yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[2-methoxy-4-(quinolin-3- 431.48 432.20 1.01 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[-(4-chloro-2-fluorophenyl)pyrimidin-2- 404.82 405.16 1.12 1yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

TABLE 2-3 HPLC Mol. Mass Ion retention IC50 (uM) ≥5.0 Weight Observedtime (min) Method 1-{[4-({4-[6-(trifluoromethyl)pyridin-3- 419.40 420.181.37 5 yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol1-{[4-({4-[2-fluoro-3-(propan-2- 426.48 427.21 1.58 5yloxy)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol1-({4-[(4-{6-fluoroimidazo[1,2-a]pyridin-2- 408.43 409.18 0.65 3yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-[(4-{[6-(4-fluorophenyl)imidazo[1,2-a]pyridin-2- 408.43 409.11 1.08 5yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan- 1-ol1-[(4-{[4-(2-chloro-5- 402.85 403.13 1.52 5fluorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(2,3- 386.39 387.18 1.45 5difluorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(3-fluoro-2- 398.43 399.20 1.46 5methoxyphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1,5-naphthyridin-3- 402.45 403.19 0.8 2yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(2-fluoro-5- 398.43 399.21 1.44 5methoxyphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-{[(2S,5R)-4-{[4-(isoquinolin-6- 429.51 430.18 0.79 9yl)phenyl]carbonyl}-2,5-dimethylpiperazin-1-yl]carbonyl}cyclopropan-1-ol 1-{[4-({6-phenylimidazo[1,2-a]pyridin-2-390.44 391.16 1.04 5 yl}carbonyl)piperazin-1-yl]carbonyl}cyclo-propan-1-ol 1-[(4-{[4-(4,5-difluoro-2- 416.42 417.18 1.49 5methoxyphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-{[(2S)-4-{[4-(4-chloro-2-fluorophenyl)- 432.87 433.04 1.29 1phenyl]carbonyl}-2-(hydroxymethyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol1-({4-[(4-phenoxyphenyl)carbonyl]piperazin-1- 366.41 367.12 1.21 9yl}carbonyl)cyclopropan-1-ol 5-fluoro-2-[4-({4-[(1- 393.41 394.17 1.15 5hydroxycyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]benzonitrile2-methoxy-2-methyl-1-{4-[(4- 366.45 367.15 1.44 8phenylphenyl)carbonyl]piperazin-1-yl}propan-1- one3,3,3-trifluoro-2-hydroxy-2-methyl-1-{4-[(4- 406.40 407.13 1.43 1phenylphenyl)carbonyl]piperazin-1-yl}propan-1- one1-[(4-{[4-(2-chloro-4- 414.88 415.17 1.52 5methoxyphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol2-hydroxy-2-methyl-1-{4-[(4- 352.43 353.14 1.24 1phenylphenyl)carbonyl]piperazin-1-yl}propan-1- one 1-[(4-{[4-(4- 364.44365.25 1.53 5 methylphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-{[4-({4-[2-chloro-5- 414.88 415.17 1.22 5(hydroxymethyl)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol1-[(4-{[2-(1,3-benzothiazol-5-yl)-4-methyl-1,3- 428.53 429.13 0.97 5thiazol-5-yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-({4-[(3-phenoxyphenyl)carbonyl]piperazin-1- 366.41 367.09 1.19 9yl}carbonyl)cyclopropan-1-ol 1-[(4-{[4-(3- 364.44 365.22 1.53 5methylphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(3-methoxypyridin-4- 381.43 382.24 0.64 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-({4-[(4-phenylphenyl)carbonyl]piperazin-1- 378.46 379.25 1.37 5yl}carbonyl)cyclopentan-1-ol 1-[(4-{[4-(1-methyl-1H-indazol-7- 404.46405.21 1.3 5 yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(6-methylpyridin-3- 365.43 366.230.58 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol(2S)-2-hydroxy-1-{4-[(4- 338.40 339.14 1.17 1phenylphenyl)carbonyl]piperazin-1- yl}propan-1-one1-{[4-({4-[5-chloro-2-(propan-2- 442.94 443.20 1.74 5yloxy)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol1-[(4-{[6-(4-chloro-2-fluorophenyl)pyridin-3- 403.84 404.14 1.22 1yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(5-fluoropyridin-3- 369.39 370.17 1.11 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(2,5- 386.39 387.18 1.46 5difluorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol2-hydroxy-1-{4-[(4- 324.37 325.16 1.1 5phenylphenyl)carbonyl]piperazin-1-yl}ethan-1-one 1-[(4-{[4-(2-fluoro-4-382.43 383.17 1.55 5 methylphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2,6-dimethoxypyridin-3- 411.45412.18 1.48 5 yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2,4-dichloro-3- 449.33 449.151.62 5 methoxyphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(5-fluoro-2- 382.43 383.20 1.53 5methylphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-olCell Proliferation Assays for FASN Inhibitors

The effects of the FASN inhibitors on cultured cancer cell proliferationwere studies with cell proliferation assays. PC3 cells were maintainedat standard culture media (F12K media supplemented with 10% fetal bovineserum, 1×MEM nonessential amino acid and 1× penicillin/streptomycin).2000-3000 cells/100 μL/well was seeded in a 96-well clear culture plate.The cells were incubated overnight in 5% CO₂ at 37° C. for attachment.Cell media were removed and replaced with F12K media containing 10%lipid reduced serum and compound. The final DMSO concentration is 0.1%.The cells were maintained in 5% CO₂ at 37° C. for 4 days. The viabilityof cells was determined by MTT assays. The IC50 of a given compound wascalculated by fitting the dose response curve with a four parameterlogistic equation.

Results

Table 3-1 lists the compounds having an IC 50<0.5 μM.

Table 3-2 lists the compounds having an IC 50≥0.5 μM.

In addition, the Molecular Weight, Mass Ion Spectrometry Results, HPLCretention time, and the Method used to synthesize the compound are alsolisted.

TABLE 3-1 HPLC Mol. Mass Ion retention IC50 (uM) <0.5 Weight Observedtime (min) Method 1-[(4-{[2-fluoro-4-(1-methyl-1H-indol-5- 421.46 422.221.29 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(isoquinolin-6- 401.17 402.02 1.48 1yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[3-chloro-4-(quinolin-3- 435.90 436.15 1.14 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol5-[2-chloro-4-({4-[(1- 448.90 449.10 1.06 5hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-3-carbonitrile 1-[(4-{[4-(quinolin-2-401.46 402.16 1.14 7 yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[3-chloro-4-(1-methyl-1H-indol-5-437.92 438.18 1.33 5 yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2-chloro-4-(1-methyl-1H-indol-5-437.92 438.15 1.32 5 yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1H-indol-4- 389.45 390.18 1.06 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[3-methyl-4-(1-methyl-1H-indol-5- 417.50 418.25 1.3 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1-benzofuran-5- 390.16 391.01 2.43 2yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol5-[4-({4-[(1- 414.46 415.15 1.09 3hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-2-carbonitrile1-({4-[(4-{imidazo[1,2-b]pyridazin-6- 391.42 392.10 0.69 7yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-[(4-{[4-(1H-indol-5- 389.17 390.06 2.11 2yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1-methyl-1H-1,3-benzodiazol-5- 404.46 405.08 0.68 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol5-[4-({4-[(1- 414.46 415.17 0.97 7hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-3-carbonitrile1-[(4-{[4-(1,3-benzothiazol-5-yl)-3- 441.93 442.12 1.16 5chlorophenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[2-fluoro-4-(6-methoxyquinolin-2- 449.47 450.15 1.25 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[2-chloro-4-(quinolin-3- 435.90 436.16 1.11 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[3-methyl-4-(quinolin-3- 415.48 416.21 1.07 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[2-fluoro-4-(quinolin-3- 419.45 420.18 1.07 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[3-chloro-4-(quinolin-6- 435.90 436.16 0.99 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(6-methoxynaphthalen-2- 430.50 431.12 1.36 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[2-fluoro-4-(7-fluoro-1H-indol-5- 425.43 426.04 1.16 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-({4-[(4-{pyrazolo[1,5-a]pyridin-2- 390.44 391.15 0.95 3yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-[(4-{[3-fluoro-4-(quinolin-3- 419.45 420.20 1.08 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1-methyl-1H-indazol-6- 404.46 405.09 1.05 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[2-fluoro-4-(quinolin-6- 419.45 420.19 0.91 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(2-methyl-2H-indazol-6- 404.46 405.08 0.94 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(quinolin-5- 401.46 402.17 0.84 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol2-[4-({4-[(1-hydroxycyclopropyl)- 416.43 417.15 1.06 4carbonyl]piperazin-1-yl}carbonyl)-phenyl]-1,3-benzoxazole-6-carbonitrile 1-[(4-{[4-(1,3-benzothiazol-6-407.49 408.14 1 2 yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1,3-benzothiazol-5- 407.49408.13 1.04 2 yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol N-{3-[4-({4-[(1-hydroxycyclopropyl)- 469.55470.08 1.04 11 carbonyl]piperazin-1-yl}-car-bonyl)phenyl]phenyl}cyclopropanesulfonamide1-({4-[(4-{1H-pyrrolo[3,2-b]pyridin-5- 390.44 391.14 0.58 2yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-[(4-{[4-(1H-indazol-3- 390.44 391.12 0.98 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[2-fluoro-4-(2-methoxyquinolin-3- 449.47 450.17 1.39 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-{[4-({3-chloro-4-[1-(trifluoromethyl)-1H-indol- 491.89 492.03 1.3 105-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol1-[(4-{[2,3-difluoro-4-(quinolin-2- 437.44 438.15 1.27 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1,3-benzothiazol-5-yl)-3- 421.51 422.16 1.13 2methylphenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1,3-dimethyl-1H-indazol-5- 418.49 419.09 1.07 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[3-methyl-4-(quinolin-6- 415.48 416.21 0.92 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1-methyl-1H-indol-2- 403.47 404.25 1.56 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-{[4-({4-[1-(trifluoromethyl)-1H-indol-5- 457.45 458.12 1.22 10yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol1-[(4-{[4-(6-chloro-1,3-benzoxazol-2- 425.87 426.11 1.33 4yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(6-methoxyquinolin-2- 431.48 432.20 1.16 5yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-olN-{3-[4-({4-[(1- 505.59 506.10 1.18 11hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}benzenesulfonamide 1-{[4-({4-[2-methoxy-5-464.43 465.17 1.43 5 (trifluoromethoxy)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol 1-[(4-{[4-(6-fluoro-1,3-benzoxazol-2-409.41 410.14 1.2 4 yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol N-{3-[4-({4-[(1-hydroxycyclopropyl)- 471.57472.19 1.08 11 carbonyl]piperazin-1-yl}carbonyl)phenyl]-phenyl}propane-2-sulfonamide 1-[(4-{[4-(isoquinolin-6- 415.19 416.041.61 1 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclobutan-1-ol1-[(4-{[4-(2,1,3-benzothiadiazol-5- 408.47 409.11 1.17 3yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1,3-benzoxazol-2- 391.42 392.16 1.14 4yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(2-methyl-2H-indazol-5- 404.46 405.17 0.88 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol5-[3-chloro-4-({4-[(1- 448.90 449.10 1.06 5hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-3-carbonitrile1-[(4-{[4-(1,3-benzothiazol-5-yl)-3- 425.48 426.12 1.1 5fluorophenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(5-fluoro-1,3-benzoxazol-2- 409.41 410.14 1.18 4yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(5-chloro-1,3-benzoxazol-2- 425.87 426.13 1.31 4yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1,3-benzothiazol-5-yl)-2- 441.93 442.11 1.14 5chlorophenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(3-chloro-2- 414.88 415.15 1.34 5methoxyphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(6-methoxy-4-methylquinolin-2- 445.51 446.16 1.16 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(2-methoxyquinolin-6- 431.18 432.08 2.28 2yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1H-1,3-benzodiazol-5- 390.44 391.20 0.6 2yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-({4-[(2-chloro-4-{imidazo[1,2-a]pyridin-2- 424.88 425.11 0.71 3yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-[(4-{[5-(1-methyl-1H-indol-5-yl)pyridin-2- 404.46 405.28 1.1 5yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol6-[4-({4-[(oxetan-2-yl)carbonyl]piperazin-1- 401.17 402.02 1.46 2yl}carbonyl)phenyl]isoquinoline 1-({4-[(4-{imidazo[1,2-a]pyridin-2-390.44 391.19 0.61 3 yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol 1-[(4-{[4-(quinolin-3- 415.19 416.04 2.13 1yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclobutan-1-ol1-[(4-{[4-(isoquinolin-1- 401.46 402.20 0.9 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-({4-[(4-{furo[3,2-b]pyridin-5- 391.42 392.08 0.97 7yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-[(4-{[4-(4-chloro-2- 402.85 403.12 1.36 1fluorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(5-chloro-2- 402.85 403.10 1.33 1fluorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1,3-benzoxazol-5- 391.42 392.16 0.97 2yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(1H-1,3-benzodiazol-4- 390.44 391.14 0.7 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(2H-1,2,3-benzotriazol-5- 391.42 392.14 0.79 3yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol1-[(4-{[4-(4-chloroquinolin-3- 435.90 436.11 1.19 7yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol3-[3-fluoro-4-({4-[(1- 435.45 436.13 0.96 5hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]quinolin-2-ol 3-[4-({4-[(1- 417.46 418.15 0.93 1hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,2-dihydroquinolin-2-one N-{3-[4-({4-[(1- 443.52444.17 0.93 11 hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}methanesulfonamide 6-[4-({4-[(1- 417.46 418.130.76 3 hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,2-dihydroquinolin-2-one1-[(4-{[4-(1-methyl-1H-indol-5-yl)-2- 471.47 472.22 1.39 5(trifluoromethyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1,3-benzothiazol-2- 407.49408.09 1.24 6 yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 5-[4-({4-[(1-hydroxycyclopropyl)- 456.54457.16 1.29 10 carbonyl]piperazin-1-yl}carbonyl)phenyl]-1-(propan-2-yl)-1H-indole-3-carbonitrile 1-[(4-{[2-chloro-4-(quinolin-6-435.90 436.14 0.96 5 yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-({4-[(2-phenyl-1,3-benzothiazol-6- 407.49408.09 1.22 5 yl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol1-[(4-{[4-(1H-1,3-benzodiazol-2- 390.44 391.14 0.73 3yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

TABLE 3-2 HPLC MOL. Mass Ion retention IC50(uM) ≥0.5 Weight Observedtime (min) Method 1-{[4-({3-chloro-4-[1-(propan-2-yl)-1H-indol-5- 465.97466.05 1.5 10 yl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol 1-{[4-({4-[2-methoxy-4-(1H-pyrazol-1-446.50 447.23 1.19 5 yl)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol5-[4-({4-[(oxetan-2-yl)carbonyl]piperazin-1- 389.45 389.18 1.03 2yl}carbonyl)phenyl]-1H-indole3-[4-({4-[(oxetan-2-yl)carbonyl]piperazin-1- 401.46 402.14 0.95 2yl}carbonyl)phenyl]quinoline 1-[(4-{[4-(2,4- 419.30 419.12 1.47, 5dichlorophenyl)phenyl]carbonyl}piperazin-1- 1.68yl)carbonyl]cyclopropan-1-ol

Enumerated Embodiments

The present disclosure also relates to the following enumeratedembodiments:

-   -   1. A fatty acid synthase inhibitor comprising the structure of        formula I:

wherein:

-   R₁ is a C₁-C₃ hydroxyl-alkyl either unsubstituted or substituted    with —CH₃ or —CH_(z)F_(3-z), 5 membered cycloalkyl either    unsubstituted or substituted with substituents selected from the    group consisting of deuterium, —R_(p), —OR_(p), —NHR_(p), and    —NR_(p)R_(p1),    -   or 3 or 4 membered cycloalkyl or heterocycloalkyl wherein (i)        the heteroatom ring member of the 3 or 4 membered        heterocycloalkyl is independently selected from O, S, or N,        and (ii) each of said 3 or 4 membered cycloalkyl or        heterocycloalkyl is either unsubstituted or optionally        substituted with substituents selected from the group consisting        of deuterium, —R_(a), —OR_(a), —NHR_(a), and —NR_(a)R_(a1);-   L is a 5-10 membered monocyclic or bicyclic alkyl or heteroalkyl    wherein (i) the heteroatom ring members of the 5-10 membered    monocyclic or bicyclic heteroalkyl are independently selected from    O, S, or N, and (ii) each of the 5-10 membered monocyclic or    bicyclic alkyl or heteroalkyl is either unsubstituted or optionally    substituted with substituents selected from the group consisting of    deuterium and —R_(b);-   A and B are independently O or S;-   Ar₁ is a 4-10 membered monocyclic or bicyclic aryl, heteroaryl or    heterocycloalkyl, wherein (i) said 4-10 membered monocyclic or    bicyclic heteroaryl or heterocycloalkyl have 1, 2, 3, or 4    heteroatoms which are independently selected from N, S or O,    and (ii) each of said 4-10 membered monocyclic or bicyclic aryl,    heteroaryl, or heterocycloalkyl is either unsubstituted or    optionally independently substituted with 1 or more substituents    which can be the same or different and are independently selected    from the group consisting of deuterium, halo, alkyl, —CH_(z)F_(3-z),    cyano, hydroxyl, hydroxylalkyl, amino, aminoalkyl-, (amino)alkoxy-,    —CONH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl),    —C(O)N(aryl)₂, —OCH_(z)F_(3-z), -alkyl, -alkenyl, -alkynyl, -alkoxy    (alkoxyalkyl)amino-, —N(R_(c))—C(O)-alkyl, —N(R_(c))—C(O)-aryl,    -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the    proviso that no two adjacent ring heteroatoms are both S or both O;-   R₂ is H or a 4-15 membered monocyclic, bicyclic or tricyclic aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered    monocyclic, bicyclic or tricyclic heteroaryl or heterocycloalkyl has    1, 2, 3, 4, 5, 6, 7 or 8 heteroatoms that are independently selected    from N, S or O, and (ii) wherein each of said aryl, heteroaryl,    cycloalkyl, or heterocycloalkyl is either unsubstituted or    optionally substituted with 1 or more substituents which can be the    same or different and are independently selected from the group    consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-,    hydroxylcycloalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-,    hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH₂,    —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl, alkoxy-, -alkenyl,    -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl,    -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl,    —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl),    —O(heteroaryl), ONH₂, —C(O)NH(alkyl), —C(O)N(aryl)₂,    —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO₂), —NH(SO₂)alkyl,    —NH(SO₂)aryl, —NH(SO₂)heteroaryl, —N(SO₂)cycloalkyl, —C(O)N(alkyl)₂,    (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O)₂-alkyl,    —S(O)₂-aryl, —S(O)₂-cycloalkyl, —C(O)N(alkyl)₂, —C(O)alkyl,    —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl,    NH—C(O)-heterocycloalkyl-R_(d), —NH—C(O)— R_(d)—(O)alkyl,    —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl,    NH₂(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl,    NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R_(d))—C(O)-alkyl,    —NH(R_(d))—C(O)-aryl, —NH(R_(d))—S(O₂)cycloalkyl, —S(O₂)NH₂,    —S(O₂)NH(alkyl), —S(O₂)N(R_(d))cycloalkyl, —S(O₂)N(alkyl)₂,    —C(O)N(H)(alkyl), —C(O)N(R_(d))(cycloalkyl), methylenedioxy,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), and -alkoxy;-   R_(p) and R_(p1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(a) and R_(a1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(b) is H, halo, C₁-C₄ alkyl, C₁-C₃ hydroxyl-alkyl, or C₃-C₄    cycloalkyl;-   R_(c) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   R_(d) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   and z is 0, 1 or 2;-   and pharmaceutically acceptable salts thereof.    -   2. A Compound of formula I:

wherein:

-   R₁ is a C₁-C₃ hydroxyl-alkyl either unsubstituted or substituted    with —CH₃ or —CH_(z)F_(3-z), 5 membered cycloalkyl either    unsubstituted or substituted with substituents selected from the    group consisting of deuterium, —R_(p), —OR_(p), —NHR_(p), and    —NR_(p)R_(p1),    -   or 3 or 4 membered cycloalkyl or heterocycloalkyl wherein (i)        the heteroatom ring member of the 3 or 4 membered        heterocycloalkyl is independently selected from O, S, or N,        and (ii) each of said 3 or 4 membered cycloalkyl or        heterocycloalkyl is either unsubstituted or optionally        substituted with substituents selected from the group consisting        of deuterium, —R_(a), —OR_(a), —NHR_(a), and —NR_(a)R_(a1);-   L is a 5-10 membered monocyclic or bicyclic alkyl or heteroalkyl    wherein (i) the heteroatom ring members of the 5-10 membered    monocyclic or bicyclic heteroalkyl are independently selected from    O, S, or N, and (ii) each of the 5-10 membered monocyclic or    bicyclic alkyl or heteroalkyl is either unsubstituted or optionally    substituted with substituents selected from the group consisting of    deuterium and —R_(b);-   A and B are independently O or S;-   Ar₁ is a 4-10 membered monocyclic or bicyclic aryl, heteroaryl or    heterocycloalkyl, wherein (i) said 4-10 membered monocyclic or    bicyclic heteroaryl or heterocycloalkyl have 1, 2, 3, or 4    heteroatoms which are independently selected from N, S or O,    and (ii) each of said 4-10 membered monocyclic or bicyclic aryl,    heteroaryl, or heterocycloalkyl is either unsubstituted or    optionally independently substituted with 1 or more substituents    which can be the same or different and are independently selected    from the group consisting of deuterium, halo, alkyl, —CH_(z)F_(3-z),    cyano, hydroxyl, hydroxylalkyl, amino, aminoalkyl-, (amino)alkoxy-,    —CONH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl),    —C(O)N(aryl)₂, —OCH_(z)F_(3-z), -alkyl, -alkenyl, -alkynyl, -alkoxy    or (alkoxyalkyl)amino-, —N(R_(c))—C(O)-alkyl, —N(R_(c))—C(O)-aryl,    -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the    proviso that no two adjacent ring heteroatoms are both S or both O;-   R₂ is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered    monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl    has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms that are independently    selected from N, S or O, and (ii) wherein each of said aryl,    heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted    or optionally substituted with 1 or more substituents which can be    the same or different and are independently selected from the group    consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-,    hydroxylcycloalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-,    hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH₂,    —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl, alkoxy-, -alkenyl,    -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl,    -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl,    —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl),    —O(heteroaryl), ONH₂, —C(O)NH(alkyl), —C(O)N(aryl)₂,    —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO₂), —NH(SO₂)alkyl,    —NH(SO₂)aryl, —NH(SO₂)heteroaryl, —N(SO₂)cycloalkyl, —C(O)N(alkyl)₂,    (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O)₂-alkyl,    —S(O)₂-aryl, —S(O)₂-cycloalkyl, —C(O)N(alkyl)₂, —C(O)alkyl,    —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl,    NH—C(O)-heterocycloalkyl-R_(d), —NH—C(O)— R_(d)—(O)alkyl,    —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl,    NH₂(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl,    NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R_(d))—C(O)-alkyl,    —NH(R_(d))—C(O)-aryl, —NH(R_(d))—S(O₂)cycloalkyl, —S(O₂)NH₂,    —S(O₂)NH(alkyl), —S(O₂)N(R_(d))cycloalkyl, —S(O₂)N(alkyl)₂,    —C(O)N(H)(alkyl), —C(O)N(R_(d))(cycloalkyl), methylenedioxy,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), and -alkoxy;-   R_(p) and R_(p1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(a) and R_(a1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(b) is H, halo, C₁-C₄ alkyl, C₁-C₃ hydroxyl-alkyl, or C₃-C₄    cycloalkyl;-   R_(c) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   R_(d) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   and z is 0, 1 or 2;-   and pharmaceutically acceptable salts thereof.    further wherein:    R₂ is not a    a substituted or unsubstituted form of

where X is N or CH;when R₁ is

connected to

position 1, and X₁ and X₂ are independently N or C—R_(z), and R_(y) andR_(z) are any substituent, then R_(x) does not include alkynyl, alkenyl,aryl, 5-14 membered heterocyclic, 5-14 membered heteroaromatic, or 4-9membered carbocyclic;when R₂ is

Ar₁ is not a substituted or unsubstituted form of

and when Ar₁ is a substituted or unsubstituted form of a 5 memberedheteroaryl, Ar₁ is

-   -   3. The compound of embodiment 1, wherein R₁ is selected from the        group consisting of:

-   -   4. The compound of embodiment 2, wherein R₁ is

-   -   5. The compound of embodiment 2, wherein R₁ is selected from the        group consisting of:

-   -   6. The compound of embodiment 2, wherein A and B are O.    -   7. The compound of embodiment 2, wherein L is:

m is 1, 2, or 3 andn is 0, 1, 2, or 3.

-   -   8. The compound of embodiment 7, wherein L is:

-   -   9. The compound of embodiment 7, wherein L is:

-   -   10. The compound of embodiment 2, wherein Ar₁ is a substituted        or unsubstituted 5-6 membered monocyclic aryl or heteroaryl.    -   11. The compound of embodiment 10, wherein Ar₁ is a substituted        or unsubstituted 5 membered monocyclic aryl or heteroaryl and        said heteroaryl has 1 or 2 heteroatoms which are independently S        or N.    -   12. The compound of embodiment 11, wherein Ar₁ is a substituted        or unsubstituted form of:

-   -   13. The compound of embodiment 10, wherein Ar₁ is a substituted        or unsubstituted 6 membered monocyclic aryl or heteroaryl and        said heteroaryl has 1 or 2 heteroatoms which are N.    -   14. The compound of embodiment 13, wherein Ar₁ is

Ph₁ is phenyl, pyridinyl, pyrazinyl, or pyrimidinyl, and

R_(e) is H, halo, or C₁-C₃ alkyl.

-   -   15. The compound of embodiment 14, wherein Ar₁ is a substituted        or unsubstituted form of:

-   -   16. The compound of embodiment 14, wherein Ar₁ is

-   -   17. The compound of embodiment 16, wherein Ar₁ is

-   -   18. The compound of embodiment 2, wherein Ar₁ is a substituted        or unsubstituted 9 membered 6,5-bicyclic heteroaryl and said        heteroaryl has 1, 2, or 3 heteroatoms which are independently O,        S or N.    -   19. The compound of embodiment 18, wherein Ar₁ is

-   -   20. The compound of embodiment 2, wherein R₂ is a substituted or        unsubstituted monocyclic or bicyclic 5-10 membered aryl or        heteroaryl.    -   21. The compound of embodiment 20, wherein R₂ is a substituted        or unsubstituted monocylic 6 membered aryl.    -   22. The compound of embodiment 21, wherein R₂ is:

-   -   23. The compound of embodiment 20, wherein R₂ is a substituted        or unsubstituted bicyclic 8-10 membered aryl or 8-10 membered        heteroaryl.    -   24. The compound of embodiment 23, wherein R₂ is a substituted        or unsubstituted 8 membered 5,5 bicyclic heteroaryl and said        heteroaryl has 1, 2, 3, or 4 heteroatoms and said heteroatoms        are independently O, S, or N.    -   25. The compound of embodiment 24, wherein R₂ is a substituted        or unsubstituted form of:

-   -   26. The compound of embodiment 20, wherein R₂ is a substituted        or unsubstituted 9 membered 6,5 bicyclic heteroaryl and said        heteroaryl has 1, 2, 3, or 4 heteroatoms and said heteroatoms        are independently O, S, or N.    -   27. The compound of embodiment 26, wherein R₂ is a substituted        or unsubstituted form of:

-   -   28. The compound of embodiment 20, wherein R₂ is a substituted        or unsubstituted 10 membered 6,6 bicyclic aryl or heteroaryl and        said heteroaryl has 1, 2, 3, or 4 heteroatoms and said        heteroatoms are O, S, or N.    -   29. The compound of embodiment 28, wherein R₂ is a substituted        or unsubstituted form of:

-   -   30. A Compound of formula I-A:

wherein:

-   R₁ is a C₁-C₃ hydroxyl-alkyl either unsubstituted or substituted    with —CH₃ or —CH_(z)F_(3-z), 5 membered cycloalkyl either    unsubstituted or substituted with substituents selected from the    group consisting of deuterium, —R_(p), —OR_(p), —NHR_(p), and    —NR_(p)R_(p1),    -   or 3 or 4 membered cycloalkyl or heterocycloalkyl wherein (i)        the heteroatom ring member of the 3 or 4 membered        heterocycloalkyl is independently selected from O, S, or N,        and (ii) each of said 3 or 4 membered cycloalkyl or        heterocycloalkyl is either unsubstituted or optionally        substituted with substituents selected from the group consisting        of deuterium, —R_(a), —OR_(a), —NHR_(a), and —NR_(a)R_(a1);-   Ar₁ is a 4-10 membered monocyclic or bicyclic aryl, heteroaryl, or    heterocycloalkyl, wherein (i) said 4-10 membered monocyclic,    bicyclic heteroaryl, or heterocycloalkyl have 1, 2, 3, or 4    heteroatoms which are independently selected from N, S or O,    and (ii) each of said 4-10 membered monocyclic or bicyclic aryl or    heteroaryl is either unsubstituted or optionally independently    substituted with 1 or more substituents which can be the same or    different and are independently selected from the group consisting    of deuterium, halo, alkyl, —CH_(z)F_(3-z), cyano, hydroxyl,    hydroxylalkyl, amino, aminoalkyl-, (amino)alkoxy-, —CONH₂,    —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂,    —OCH_(z)F_(3-z), -alkyl, -alkenyl, -alkynyl, -alkoxy or    (alkoxyalkyl)amino-, —N(R_(c))—C(O)-alkyl, —N(R_(c))—C(O)-aryl,    -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the    proviso that no two adjacent ring heteroatoms are both S or both O;-   R₂ is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered    monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl    has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently    selected from N, S or O, and (ii) wherein each of said aryl,    heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted    or optionally substituted with 1 or more substituents which can be    the same or different and are independently selected from the group    consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-,    hydroxylcycloalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-,    hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH₂,    —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl, alkoxy-, -alkenyl,    -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl,    -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl,    —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl),    —O(heteroaryl), ONH₂, —C(O)NH(alkyl), —C(O)N(aryl)₂,    —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO₂), —NH(SO₂)alkyl,    —NH(SO₂)aryl, —NH(SO₂)heteroaryl, —N(SO₂)cycloalkyl, —C(O)N(alkyl)₂,    (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O)₂-alkyl,    —S(O)₂-aryl, —S(O)₂-cycloalkyl, —C(O)N(alkyl)₂, —C(O)alkyl,    —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl,    NH—C(O)-heterocycloalkyl-R_(d), —NH—C(O)— R_(d)—(O)alkyl,    —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl,    NH₂(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl,    NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R_(d))—C(O)-alkyl,    —NH(R_(d))—C(O)-aryl, —NH(R_(d))—S(O₂)cycloalkyl, —S(O₂)NH₂,    —S(O₂)NH(alkyl), —S(O₂)N(R_(d))cycloalkyl, —S(O₂)N(alkyl)₂,    —C(O)N(H)(alkyl), —C(O)N(R_(d))(cycloalkyl), methylenedioxy,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), and -alkoxy;-   R_(p) and R_(p1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(a) and R_(a1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(c) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   R_(d) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   and z is 0, 1 or 2;-   and pharmaceutically acceptable salts thereof.    -   31. The compound of embodiment 30, wherein R₁ is

-   -   32. A Compound of formula I-B:

wherein:

-   Ar₁ is a 4-10 membered monocyclic or bicyclic aryl, heteroaryl, or    heterocycloalkyl, wherein (i) said 4-10 membered monocyclic or    bicyclic heteroaryl or heterocycloalkyl have 1, 2, 3, or 4    heteroatoms which are independently selected from N, S, or O,    and (ii) each of said 4-10 membered monocyclic or bicyclic aryl or    heteroaryl is either unsubstituted or optionally independently    substituted with 1 or more substituents which can be the same or    different and are independently selected from the group consisting    of deuterium, halo, alkyl, —CH_(z)F_(3-z), cyano, hydroxyl,    hydroxylalkyl, amino, aminoalkyl-, (amino)alkoxy-, —CONH₂,    —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂,    —OCH_(z)F_(3-z), -alkyl, -alkenyl, -alkynyl, -alkoxy or    (alkoxyalkyl)amino-, —N(R_(c))—C(O)-alkyl, —N(R_(c))—C(O)-aryl,    -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the    proviso that no two adjacent ring heteroatoms are both S or both O;-   R₂ is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered    monocyclic, bicyclic, tricyclic heteroaryl or heterocycloalkyl has    1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently    selected from N, S, or O, and (ii) wherein each of said aryl,    heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted    or optionally substituted with 1 or more substituents which can be    the same or different and are independently selected from the group    consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-,    hydroxylcycloalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-,    hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH₂,    —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl, alkoxy-, -alkenyl,    -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl,    -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl,    —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl),    —O(heteroaryl), ONH₂, —C(O)NH(alkyl), —C(O)N(aryl)₂,    —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO₂), —NH(SO₂)alkyl,    —NH(SO₂)aryl, —NH(SO₂)heteroaryl, —N(SO₂)cycloalkyl, —C(O)N(alkyl)₂,    (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O)₂-alkyl,    —S(O)₂-aryl, —S(O)₂-cycloalkyl, —C(O)N(alkyl)₂, —C(O)alkyl,    —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl,    NH—C(O)-heterocycloalkyl-R_(d), —NH—C(O)— R_(d)—(O)alkyl,    —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl,    NH₂(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl,    NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R_(d))—C(O)-alkyl,    —NH(R_(d))—C(O)-aryl, —NH(R_(d))—S(O₂)cycloalkyl, —S(O₂)NH₂,    —S(O₂)NH(alkyl), —S(O₂)N(R_(d))cycloalkyl, —S(O₂)N(alkyl)₂,    —C(O)N(H)(alkyl), —C(O)N(R_(d))(cycloalkyl), methylenedioxy,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), and -alkoxy;-   R_(c) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   R_(d) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   and z is 0, 1 or 2;-   and pharmaceutically acceptable salts thereof.    -   33. A Compound of formula I-C:

wherein:

-   R₁ is a C₁-C₃ hydroxyl-alkyl either unsubstituted or substituted    with —CH₃ or —CH_(z)F_(3-z), 5 membered cycloalkyl either    unsubstituted or substituted with substituents selected from the    group consisting of deuterium, —R_(p), —OR_(p), —NHR_(p), and    —NR_(p)R_(p1),    -   or 3 or 4 membered cycloalkyl or heterocycloalkyl wherein (i)        the heteroatom ring member of the 3 or 4 membered        heterocycloalkyl is independently selected from O, S, or N,        and (ii) each of said 3 or 4 membered cycloalkyl or        heterocycloalkyl is either unsubstituted or optionally        substituted with substituents selected from the group consisting        of deuterium, —R_(a), —OR_(a), —NHR_(a), and —NR_(a)R_(a1);-   R₂ is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered    monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl    has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently    selected from N, S or O, and (ii) wherein each of said aryl,    heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted    or optionally substituted with 1 or more substituents which can be    the same or different and are independently selected from the group    consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-,    hydroxylcycloalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-,    hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH₂,    —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl, alkoxy-, -alkenyl,    -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl,    -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl,    —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl),    —O(heteroaryl), ONH₂, —C(O)NH(alkyl), —C(O)N(aryl)₂,    —C(O)NH(cycloalkyl), NH₂(CO)cycloalkyl-, —NH(CO)cycloalkyl,    —NH(SO₂), —NH(SO₂)alkyl, —NH(SO₂)aryl, —NH(SO₂)heteroaryl,    —N(SO₂)cycloalkyl, —C(O)N(alkyl)₂, (aryl)alkyl-, -heteroaryl,    (heteroaryl)alkyl-, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-cycloalkyl,    —C(O)N(alkyl)₂, —C(O)alkyl, —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl,    NH—C(O)-heterocycloalkyl, NH—C(O)-heterocycloalkyl-R_(d), —NH—C(O)—    R_(d)—(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl,    NH—C(O)—NH-cycloalkyl, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl,    NH—C(O)—NH-cycloalkyl, —NH—C(O)—O— cycloalkyl,    —NH(R_(d))—C(O)-alkyl, —NH(R_(d))—C(O)-aryl,    —NH(R_(d))—S(O₂)cycloalkyl, —S(O₂)NH₂, —S(O₂)NH(alkyl),    —S(O₂)N(R_(d))cycloalkyl, —S(O₂)N(alkyl)₂, —C(O)N(H)(alkyl),    —C(O)N(R_(d))(cycloalkyl), methylenedioxy, —CH_(z)F_(3-z),    —OCH_(z)F_(3-z), and -alkoxy;-   R_(p) and R_(p1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(a) and R_(a1) are independently H, halo, C₁-C₄ alkyl, or C₃-C₄    cycloalkyl;-   R_(d) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   R_(q) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   and z is 0, 1 or 2;-   and pharmaceutically acceptable salts thereof.    -   34. The compound of embodiment 33, wherein R₁ is

-   -   35. A compound of formula I-D:

wherein:

-   R₁′ is OH or NH₂;-   R₂ is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered    monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl    has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently    selected from N, S or O, and (ii) wherein each of said aryl,    heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted    or optionally substituted with 1 or more substituents which can be    the same or different and are independently selected from the group    consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-,    hydroxylcycloalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-,    hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH₂,    —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂,    —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl, alkoxy-, -alkenyl,    -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl,    -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl,    —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl),    —O(heteroaryl), ONH₂, —C(O)NH(alkyl), —C(O)N(aryl)₂,    —C(O)NH(cycloalkyl), NH₂(CO)cycloalkyl-, —NH(CO)cycloalkyl,    —NH(SO₂), —NH(SO₂)alkyl, —NH(SO₂)aryl, —NH(SO₂)heteroaryl,    —N(SO₂)cycloalkyl, —C(O)N(alkyl)₂, (aryl)alkyl-, -heteroaryl,    (heteroaryl)alkyl-, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-cycloalkyl,    —C(O)N(alkyl)₂, —C(O)alkyl, —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl,    NH—C(O)-heterocycloalkyl, NH—C(O)-heterocycloalkyl-R_(d), —NH—C(O)—    R_(d)—(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl,    NH—C(O)—NH-cycloalkyl, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl,    NH—C(O)—NH-cycloalkyl, —NH—C(O)—O— cycloalkyl,    —NH(R_(d))—C(O)-alkyl, —NH(R_(d))—C(O)-aryl,    —NH(R_(d))—S(O₂)cycloalkyl, —S(O₂)NH₂, —S(O₂)NH(alkyl),    —S(O₂)N(R_(d))cycloalkyl, —S(O₂)N(alkyl)₂, —C(O)N(H)(alkyl),    —C(O)N(R_(d))(cycloalkyl), methylenedioxy, —CH_(z)F_(3-z),    —OCH_(z)F_(3-z), and -alkoxy;-   R_(d) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   R_(q) is H, halo, C₁-C₄ alkyl, or C₃-C₄ cycloalkyl;-   and z is 0, 1 or 2;-   and pharmaceutically acceptable salts thereof.    -   36. The compounds of embodiment 35, wherein R₂ is a:-   6 membered aryl either unsubstituted or optionally substituted with    1 or more substituents which can be the same or different and are    independently selected from the group consisting of deuterium, halo,    cyano, alkyl, aryl, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-cycloalkyl,    —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl,    NH—C(O)-heterocycloalkyl-R_(d), —NH—C(O)— R_(d)—(O)alkyl,    —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl,    NH₂(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl,    NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R_(d))—C(O)-alkyl,    —NH(R_(d))—C(O)-aryl, —NH(R_(d))—S(O₂)cycloalkyl, —S(O₂)NH₂,    —S(O₂)NH(alkyl), —S(O₂)N(R_(d))cycloalkyl, —S(O₂)N(alkyl)₂,    —C(O)N(H)(alkyl), and —C(O)N(R_(d))(cycloalkyl); or-   9 membered bicyclic heteroaryl having 1, 2, or 3 or 4 heteroatoms    which are independently selected from N, S or O, and wherein each of    said heteroaryl, is either unsubstituted or optionally substituted    with 1 or more substituents which can be the same or different and    are independently selected from the group consisting of deuterium,    halo, cyano, alkyl, aryl, —S(O)₂-alkyl, —S(O)₂-aryl,    —S(O)₂-cycloalkyl, —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl,    NH—C(O)-heterocycloalkyl, NH—C(O)-heterocycloalkyl-R_(d), —NH—C(O)—    R_(d)—(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl,    NH—C(O)—NH-cycloalkyl, NH₂(CO)cycloalkyl-, NH—C(O)—NH-aryl,    —NH—C(O)—O-alkyl, NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl,    —NH(R_(d))—C(O)-alkyl, —NH(R_(d))—C(O)-aryl,    —NH(R_(d))—S(O₂)cycloalkyl, —S(O₂)NH₂, —S(O₂)NH(alkyl),    —S(O₂)N(R_(d))cycloalkyl, —S(O₂)N(alkyl)₂, —C(O)N(H)(alkyl), and    —C(O)N(R_(d))(cycloalkyl).    -   37. A compound selected from:

IUPAC Name Compound Structure 1-({4-[(4-phenylphenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol

2-hydroxy-2-methyl-1-(4-[(4- phenylphenyl)carbonyl]piperazin-1-yl)propan-1-one

2-hydroxy-1-{4-[(4- phenylphenyl)carbonyl]piperazin-1- yl}ethan-1-one

1-({4-[(4- phenylphenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopentan-1-ol

3,3,3-trifluoro-2-hydroxy-2-methyl-1- {4-[(4-phenylphenyl)carbonyl]piperazin-1- yl}propan-1-one

1-[(4-{[4-(3- methylphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(4- methylphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-fluoro-3- methoxyphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-fluoro-4- methylphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-fluoro-4- methoxyphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-chloro-4- fluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(3-chloro-4- fluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(4-chloro-2- fluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2,4- dichlorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5-fluoro-2- methylphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(3-fluoro-4- methylphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2,3- dichlorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2,5- dichlorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(4-chloro-3- fluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2,5- difluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(3,4- dichlorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2,3- difluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-methyl-1H-indol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(2-fluoro-5- methylphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[2-chloro-5- (trifluoromethyl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(4-chloro-2- methoxyphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(3-chloro-2- methoxyphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(4,5-difluoro-2- methoxyphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[2-fluoro-3- (trifluoromethyl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[4-chloro-2- (trifluromethyl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(2-chloro-4- methoxyphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[5-chloro-2-(propan-2- ylozy)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[3-fluoro-5- (trifluoromethyl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cycloproan-1-ol

1-{[4-({4-[2-methoxy-5- (trifluoromethoxy)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(3-fluoro-2- methoxyphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(3-methoxypyridin-4- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(quinolin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(isoquinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-({4-[(4-{imidazo[1,2-a]pyridin-6- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-[(4-{[4-(1,3-benzothiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[6-(trifluoromethyl)pyridin-3- yl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(5-chloro-2- fluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(6-methylpyridin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2,6-dimethoxypyridin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5-fluoropyridin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-methyl-1H-indol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-chloro-5- fluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-fluoro-5- methoxyphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-fluoro-3- methylphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[4-fluoro-2- (trifluoromethyl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[2-chloro-5- (hydroxymethyl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(2-methyl-2H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-methyl-1H-indazol-7- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1H-indol-4- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

N-cyclopropyl-3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]benzamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}ethane- 1-sulfonamide

4-fluoro-3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-N- methylbenzamide

4-fluoro-3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-N-(propan-2- yl)benzamide

1-[(4-{[4-(2,4-dichloro-3- methoxyphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[2-fluoro-3-(propan-2- yloxy)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[2-fluoro-3- (trfluoromethoxy)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[3- (cyclopropylmethoxy)phenyl]phenyl} carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

5-fluoro-2-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]benzonitrile

1-[(4-{[4-(1-methyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-methyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[6-(1-methyl-1H-indol-5- yl)pyridin-3-yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[5-(1-methyl-1H-indol-5- yl)pyridin-2-yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-fluoro-4-(1-methyl-1H-indol- 5-yl)phenyl]carbonyl}piperain-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-fluoro-4-(quinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

2-methoxy-2-methyl-1-{4-[(4- phenylphenyl)carbonyl]piperazin-1-yl}propane-1-one

(2S)-2-hydroxy-1-{4-[(4- phenylphenyl)carbonyl]piperazin-1-yl}propan-1-one

1-[(4-{[4-(quinolin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

1-[(4-{[2-chloro-4-(quinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-chloro-4-(1-methyl-1H-indol- 5-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[6-(quinolin-6-yl)pyridin-3- yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-methyl-2-(1-methyl-1H-indol- 5-yl)-1,3-thiazol-5-yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-methyl-2-(quinolin-3-yl)-1,3-thiazol-5-yl]carbonyl}piperazin-1- yl)carbonyl]cycloopropan-1-ol

1-[(4-{[2-(1,3-benzothiazol-5-yl)-4- methyl-1,3-thiazol-5-yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[3-fluoro-4-(quinolin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[3-fluoro-4-(quinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-benzothiazol-5-yl)-3- fluorophenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[3-methyl-4-(1-methyl-1H-indol- 5-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[3-methyl-4-(quinolin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[3-methyl-4-(quinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-benzothiazol-5-yl)-3- methylphenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-chloro-4-(quinolin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-benzothiazol-5-yl)-2- chlorophenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[3-chloro-4-(1-methyl-1H-indol- 5-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[3-chloro-4-(quinolin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[3-chloro-4-(quinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-benzothiazol-5-yl)-3- chlorophenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-methyl-1H-indol-5-yl)-2- (trifluoromethyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(quinolin-6-yl)-2- (trifluoromethyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[3-methoxy-4-(quinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-methoxy-4-(quinolin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-methoxy-4-(quinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-benzothiazol-5-yl)-2- methoxyphenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[5-(quinolin-6-yl)pyrimidin-2- yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[5-(1-methyl-1H-indol-5- yl)pyrazin-2-yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[5-(quinolin-3-yl)pyrazin-2- yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[5-(quinolin-6-yl)pyrazin-2- yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-({4-[(4- phenylphenyl)carbonyl]piperazin-1-yl}carbonyl)cyclobutan-1-ol

1-[(4-{[4-(isoquinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

1-{[(2S,5R)-4-{[4-(isoquinolin-6- yl)phenyl]carbonyl}-2,5-dimethylpiperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(1H-indol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

3-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]quinoline

5-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole

1-[(4-{[2-fluoro-4-(quinolin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

6-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]isoquinoline

1-[(4-{[4-(1,5-naphthyridin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-benzofuran-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-({4-[(4- phenoxyphenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-[(4-{[2-fluoro-4-(7-fluoro-1H-indol- 5-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({3-chloro-4-[1-(trifluoromethyl)- 1H-indol-5-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(1,3-benzoxazol-5- yl)phenyl]carbonyl}piperazin-1yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-benzothiazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({3-chloro-4-[1-(propan-2-yl)- 1H-indol-5-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cycloprpoan-1-ol

1-[(4-{[4-(1H-1,3-benzodiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

5-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H- indole-3-carbonitrile

3-[3-fluoro-4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl] quinolin-2-ol

1-[(4-{[4-(1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-fluoro-4-(2-methoxyquinolin- 3-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(4-chloroquinolin-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(7-fluoro-1H-indol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(quinolin-2- yl)phenyl]carbonyl}piperazin-1yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-benzothiazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-methoxyquinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbanyl]cyclopropan-1-ol

1-{[4-({4-[1-(trifluormomethyl)-1H-indol-5-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(6-methoxynaphthalen-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5-chloro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(6-chloro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5-fluoro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(6-fluoro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(6-methoxynaphthalen-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5-chloro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(6-chloro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5-fluoro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-ol

1-[(4-{[4-(6-fluoro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-({4-[(4-{pyrazolol[1,5-a]pyridin-2- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-{[4-({4-[1-(propan-2-yl)-1H-indazol- 5-yl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-[(4-{[6-(2-methoxyquinolin-6- yl)pyridin-3-yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[5-(2-methoxyquinolin-6- yl)pyridin-2-yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({6-phenylimidazo[1,2-a]pyridin- 2-yl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-[(4-{[6-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[5-(4-chloro-2- fluorophenyl)pyridin-2- yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[6-(4-chloro-2- fluorophenyl)pyridin-3- yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[5-(4-chloro-2- fluorophenyl)pyrimidin-2-yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-fluoro-4-(6-fluoroquinolin-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2-fluoro-4-(6-methoxyquinolin- 2-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2,3-difluoro-4-(quinolin-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2,3-difluoro-4-(6- fluoroquinolin-2-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[2,3-difluoro-4-(6- methoxyquinolon-2-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(6-fluoroquinolin-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(6-methoxyquinolin-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-({4-[(4-{imidazol[1,2-a]pyridin-2- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-[(4-{[4-(2,1,3-benzoxadiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} benzenesulfonamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl] phenyl}methanesulfonamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl] phenyl}propane-2-sulfonamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl] phenyl}cyclopropanesulfonamide

1-[(4-{[4-(isoquinolin-1- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[7-(trifluoromethyl)quinolin-4-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(6-methoxy-4-methylquinolin-2-yl)phenyl]cardbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5-chloro-1H-1,3- benzodiazol-2-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(4-chloro-1H-1,3- benzodiazol-2-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5,6-difluoro-1H-1,3- benzodiazol-2-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5-methoxy-1H-1,3- benzodiazol-2-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(5-fluoro-1H-1,3-benzodiazol-2-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-dimethyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

6-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-2,3-dihydro- 1,3-benzoxazol-2-one

5-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-2,3-dihydro- 1,3-benzoxazol-2-one

1-[(4-{[4-(3-methyl-1,2-benzoxazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1H-1,3-benzodiazol-4- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-benzoxazol-4- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(quinolin-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1H-indazol-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-({4-[(4-{furo[3,2-b]pyridin-5- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-({4-[(4-{furo[3,2-c]pyridin-4- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-({4-[(4-{[1,2,4]triazolo[4,3- b]pyridazin-6-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol

1-({4-[(4-{imidazo[1,2-a]pyrazin-6- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-({4-[(4-{1H-pyrrolo[3,2-b]pyridin-5- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-({4-[(4-{imidazol[1,2-b]pyridazin-6- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-[(4-{[4-(1-methyl-1H-1,3- benzodiazol-5-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2,1,3-benzothiadiazol-4- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[2- (trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-({4-[(4-{6-chloroimidazo[1,2- a]pyridin-3-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol

1-[(4-{[4-(2-methyl-2H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-({4-[(4-{imidazo[1,2-a]pyrimidin-7- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

5-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-2- carbonitrile

2-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,3- benzoxazole-6-carbonitrile

1-[(4-{[4-(2,1,3-benzothiadiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2H-1,2,3-benzotriazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-({4-[(2-phenyl-1,3-benzothiazol-6- yl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-[(4-{[2-(4-fluorophenyl)-1,3- benzothiazol-6-yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

2-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,3- benzoxazole-5-carbonitrile

3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,2- dihydroquinolin-2-one

1-({4-[(2-chloro-4-{imidazo[1,2- a]pyridin-2-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol

1-({4-[(3- phenoxyphenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-({4-[(4-{6-fluoroimidazo[1,2- a]pyridin-2-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol

1-({4-[(4-{6-methoxyimidazo[1,2- a]pyridin-2-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclopropanecarboxamide

1-{[(2S)-4-{[4-(4-chloro-2- fluorophenyl)phenyl]carbonyl}-2-(hydroxymethyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(3- cyclopropoxyphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cycloproan-1-ol

N-cyclopropyl-3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]benzene-1- sulfonamide

5-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]1H-indole-2- carboxamide

1-[(4-{[4-(3- chlorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(4- chlorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[(3S)-4-{[4-(4-chloro-2- fluorophenyl)phenyl]carbonyl}-3-(hydroxymethyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(1H-indol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-({4-[(4-{3-chloroimidazo[1,2- a]pyridin-2-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol

1-[(4-{[4-(1-methyl-1H-1,3- benzodiazol-2-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

3-[3-chloro-4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-N- cyclopropylbenzene-1-sulfonamide

1-({4-[(2-chloro-4-{furo[3,2-b]pyridin-5-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol

1-[(4-{[2-chloro-4-(1-methyl-1H-1,3- benzodiazol-5-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

N-{3-[3-chloro-4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl] phenyl}cyclopropanesulfonamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl] phenyl}cyclobutanecarboxamide

1-{[4-({4-[3- (cyclopropanesulfonyl)phenyl]phenyl} carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

N-{5-[3-chloro-4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]pyridin-3- yl}cyclopropanesulfonamide

N-{5-[3,chloro-4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]pyridin-3- yl}cyclopropanecarboxamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl] piperazin-1-yl}carbonyl)phenyl]phenyl} oxetane-3-carboxamide

1-{[4-({4-[3- (cyclopropanesulfonyl)phenyl]phenyl} carbonyl)piperazin-1-yl]carbonyl}cyclobutan-1-ol

1-({4-[3- (cyclopropanesulfonyl)phenyl]phenyl} carbonyl)-4-[(oxetan-2-yl)carbonyl]piperazine

1-({4-[(4-{3-chloroimidazo[1,2- a]pyridin-2-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclobutan-1-ol

1-[(4-{3-chloroimidazo[1,2-a]pyridin-2-yl}phenyl)carbonyl]-4-[(oxetan-2- yl)carbonyl]piperazine

1-[(4-{[4-(3- cyclopropoxyphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1- ol

1-{[4-(3- cyclopropoxyphenyl)phenyl]carbonyl}-4-[(oxetan-2-yl)carbonyl]piperazine

N-{3-[4-({4-[(1- hydroxycyclobutyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclopropanecarboxamide

N-{3-[4-({4-[(oxetane-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclopropanecarboxamide

3-[4-({4-[(1- hydroxycyclobutyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,2- dihydroquinolin-2-one

3-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1- yl}carbonyl)phenyl]1,2-dihydroquinolin-2-one

5-[4-({4-[(1- hydroxycyclobutyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-2- carbonitrile

5-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-2- carbonitrile

1-[(4-{[4-(1-methyl-1H-1,3- benzodiazol-5-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclobutan-1-ol

1-methyl-5-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-1,3- benzodiazole

1-({4-[(4-{imidazol[1,2-b]pyridazin-6- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclobutan-1-ol

1-[(4-{imidazo[1,2-b]pyridazin-6- yl}phenyl)carbonyl]-4-[(oxetan-2-yl)carbonyl]piperazine

1-({4-[(4-{furo[3,2-b]pyridin-5- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclobutan-1-ol

1-[(4-{furo[3,2-b]pyridin-5- yl}phenyl)carbonyl]-4-[(oxetan-2-yl)carbonyl]piperazine

1-[(4-{[4-(1H-indazol-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

3-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indazole

1-[(4-{[4-(1,3-dimethyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

1,3-dimethyl-5-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indazole

N-{3-[4-({4-[(1- hydroxycyclobutyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclopropanesulfonamide

N-{3-[4-([4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclopropanesulfonamide

1-[(4-{[4-(6-fluoro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

6-fluoro-2-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,3-benzoxazole

1-[(4-{[4-(6-chloro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

6-chloro-2-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,3-benzoxazole

5-[4-({4-[(1- hydroxycyclobutyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-3- carbonitrile

5-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-3- carbonitrile

1-[(4-{[4-(1,3-benzothiazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

2-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,3-benzothiazole

1-[(4-{[4-(quinolin-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

2-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]quinoline

1-[(4-{[4-(1H-1,3-benzodiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

5-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-1,3- benzodiazole

1-[(4-{[4-(1,3-benzothiazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

6-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,3-benzothiazole

1-[(4-{[4-(1,3-benzoxazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

5-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,3-benzoxazole

1-[(4-{[4-(1,3-benzothiazole-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

5-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,3-benzothiazole

1-[(4-{[4-(1-methyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

1-methyl-6-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indazole

N-cyclopropyl-3-[4-({4-[(1- hydroxycyclobutyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]benzamide

N-cyclopropyl-3-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]benzamide

1-[(4-{[4-(2-methyl-2H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

2-methyl-6-[4-({4-[(oxetan-2- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-2H-indazole

1-[(4-{[4-(4-chloro-2- fluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

1-{[4-(4-chloro-2- fluorophenyl)phenyl]carbonyl}-4-[(oxetan-2-yl)carbonyl]piperazine

1-[(4-{[4-(5-chloro-2- fluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-ol

1-{[4-(5-chloro-2- fluorophenyl)phenyl]carbonyl}-4-[(oxetan-2-yl)carbonyl]piperazine

1-{[4-({4-[3- (cyclopropanesulfonyl)phenyl]phenyl} carbonyl)piperazin-1-yl]carbonyl}cyclobutan-1-amine

1-{[4-({4-[3- (cyclopropanesulfonyl)phenyl]phenyl} carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-amine

1-({4-[(4-{3-chloroimidazo[1,2- a]pyridin-2-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclobutan-1-amine

1-({4-[(4-{3-chloroimidazo[1,2- a]pyridin-2-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-amine

1-[(4-{[4-(3- cyclopropoxyphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1- amine

1-[(4-{[4-(3- cyclopropoxyphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1- amine

N-{3-[4-({4-[(1- aminocyclobutyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclopropanecarboxamide

N-{3-[4-({4-[(1- aminocyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclopropanecarboxamide

3-[4-({4-[(1- aminocyclobutyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,2- dihydroquinolin-2-one

3-[4-({4-[(1- aminocyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,2- dihydroquinolin-2-one

5-[4-({4-[(1- aminocyclobutyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-2- carbonitrile

5-[4-({4-[(1- aminocyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-2- carbonitrile

1-[(4-{[4-(1-methyl-1H-1,3- benzodiazol-5-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(1-methyl-1H-1,3- benzodiazol-5-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-amine

1-({4-[(4-{imidazo[1,2-b]pyridazin-6- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclobutan-1-amine

1-({4-[(4-{imidazo[1,2-b]pyridazin-6- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-amine

1-({4-[(4-{furo[3,2-b]pyridin-5- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclobutan-1-amine

1-({4-[(4-{furo[3,2-b]pyridin-5- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-amine

1-[(4-{[4-(1H-indazol-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl}cyclobutan-1-amine

1-[(4-{[4-(1H-indazol-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(1,3-dimethyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(1,3-dimethyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

N-{3-[4-({4-[(1- aminocyclobutyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclopropanesulfonamide

N-{3-[4-({4-[(1- aminocyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclopropanesulfonamide

1-[(4-{[4-(6-fluoro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(6-fluoro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(6-chloro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(6-chloro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

5-[4-({4-[(1- aminocyclobutyl)carbonyl]piperzin-1-yl}carbonyl)phenyl]-1H-indole-3- carbonitrile

5-[4-({4-[(1- aminocyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-3- carbonitrile

1-[(4-{[4-(1,3-benzothiazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(1,3-benzothiazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(quinolin-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(quinolin-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(1H-1,3-benzodiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(1H-1,3-benzodiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(1,3-benzothiazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(1,3-benzothiazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(1,3-benzoxazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(1,3-benzoxazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(1,3-benzothiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(1,3-benzothiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(1-methyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(1-methyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

3-[4-({4-[(1- aminocyclobutyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-N- cyclopropylbenzamide

3-[4-({4-[(1- aminocyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-N- cyclopropylbenzamide

1-[(4-{[4-(2-methyl-2H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(2-methyl-2H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(4-chloro-2- fluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(4-chloro-2- fluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

1-[(4-{[4-(5-chloro-2- fluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclobutan-1-amine

1-[(4-{[4-(5-chloro-2- fluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-amine

3-{[4-({4-[3- (cyclopropanesulfonyl)phenyl]phenyl} carbonyl)piperazin-1-yl]carbonyl}oxetan-3-ol

3-{[4-({4-[3- (cyclopropanesulfonyl)phenyl]phenyl} carbonyl)piperazin-1-yl]carbonyl}oxetan-3-amine

3-({4-[(4-{3-chloroimidazo[1,2- a]pyridin-2-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)oxetan-3-ol

3-({4-[(4-{3-chloroimidazo[1,2- a]pyridin-2-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)oxetan-3-amine

3-[(4-{[4-(3- cyclopropoxyphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(3- cyclopropoxyphenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3- amine

N-{3-[4-({4-[(3-hydroxyoxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclopropanecarboxamide

N-{3-[4-({4-[(3-aminooxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclopropanecarboxamide

3-[4-({4-[(3-hydroxyoxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,2- dihydroquinolin-2-one

3-[4-({4-[(3-aminooxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1,2- dihydroquinolin-2-one

5-[4-({4-[(3-hydroxyoxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-2- carbonitrile

5-[4-({4-[(3-aminooxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-2- carbonitrile

3-[(4-{[4-(1-methyl-1H-1,3- benzodiazol-5-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(1-methyl-1H-1,3- benzodiazol-5-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]oxetan-3-amine

3-({4-[(4-{imidazol[1,2-b]pyrdiazin-6- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)oxetan-3-ol

3-({4-[(4-{imidazo[1,2-b]pyridazin-6- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)oxetan-3-amine

3-({4-[(4-{furo[3,2-b]pyridin-5- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)oxetan-3-ol

3-({4-[(4-{furo[3,2-b]pyridin-5- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)oxetan-3-amine

3-[(4-{[4-(1H-indazol-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(1H-indazol-3- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(1,3-dimethyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(1,3-dimethyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

N-{3-[4-({4-[(3-hydroxyoxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclopropanesulfonamide

N-{3-[4-({4-[(3-aminooxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclopropanesulfonamide

3-[(4-{[4-(6-fluoro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(6-fluoro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperain-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(6-chloro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(6-chloro-1,3-benzoxazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

5-[4-({4-[(3-hydroxyoxetan-3- yl)carbonyl]piperazin-1-yl}cadrbonyl)phenyl]-1H-indole-3- carbonitrile

5-[4-({4-[(3-aminooxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indole-3- carbonitrile

3-[(4-{[4-(1,3-benzothiazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(1,3-benzothiazol-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(quinolin-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(quinolin-2- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(1H-1,3-benzodiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(1H-1,3-benzodiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(1,3-benzothiazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(1,3-benzothiazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(1,3-benzoxazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(1,3-benzoxazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(1,3-benzothiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(1,3-benzothiazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(1-methyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(1-methyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

N-cyclopropyl-3-[4-({4-[(3- hydroxyoxetan-3-yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]benzamide

3-[4-({4-[(3-aminooxetan-3- yl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-N- cyclopropylbenzamide

3-[(4-{[4-(2-methyl-2H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(2-methyl-2H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(4-chloro-2- fluorophenyl)pheny]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(4-chloro-2- fluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

3-[(4-{[4-(5-chloro-2- fluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-ol

3-[(4-{[4-(5-chloro-2- fluorophenyl)phenyl]carbonyl}piperazin-1-yl)carbonyl]oxetan-3-amine

1-({4-[(4-{5-chloro-[1,3]thiazolo[5,4- d][1,3]thiazol-2-yl}ohenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol

1-{[4-({4-[4-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-({4-[(4-{imidazo[2,1- b][1,3,4]thiadiazol-2-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol

1-({4-[(4-{6H-thieno[2,3-b]pyrrol-2- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

1-({4-[(4-{4H-thieno[3,2-b]pyrrol-3- yl}phenyl)carbonyl]piperazin-1-yl}carbonyl)cyclopropan-1-ol

2-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-3H-pyrrolizin- 3-one

6-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-3H-pyrrolizin- 3-one

1-[(4-{[4-(1-methanesulfonyl-1H-indol- 6-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[4-(1-methyl-1H-pyrazol-3-yl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]phenyl}carbonyl)piperazin-1- yl)carbonyl}cyclopropan-1-ol

1-[(4-{[4-(1-ethyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-cyclobutyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[1-(oxetan-3-yl)-1H-indazol- 5-yl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(propan-2-yl)-1H-indazol- 5-yl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(2-methoxyethyl)-1H- indazol-5-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(cyclopropylmethyl)-1H- indazol-5-yl]phenyl}cadrbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(1-propyl-1H-indazol-5- yl)phenyl]carbonyl]piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[1-(cyclobutylmethyl)-1H- indazol-5-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(oxetan-3-ylmethyl)-1H- indazol-5-yl]phenyl}carbonyl)piperazin-1- yl]cabonyl}cyclopropan-1-ol

1-{[4-({4-[1-(2-hydroxyethyl)-1H- indazol-5-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[4-(1H-pyrazol-5- yl)phenyl]phenyl}carbonyl)piperazin-1yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[4-(1H-pyrazol-4- yl)phenyl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[4-(2-methyl-2H-1,2,3- triazol-4-yl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[4-(1-methyl-1H-1,2,3- triazol-4-yl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(1-methanesulfonyl-1H-indol- 5-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[1-(cyclopropanesulfonyl)- 1H-indol-5-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(cyclopropanesulfonyl)- 1H-indol-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[2-(hydroxymethyl)-1H- indol-5-yl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

2-{5-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1H-indol-3- yl}acetonitrile

1-{[4-({4-[3-(2-hydroxyethyl)-1H-indol-5-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

5-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-1-benzofuran- 2-carbonitrile

1-[(4-{[4-(3-amino-1-methyl-1H- indazol-6-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-aminoisoquinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(3-aminoisoquinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1,3-dimethylisoquinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[3-(methoxymethyl)-1- methyl-1H-indazol-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[3-(hydroxymethyl)-1- methyl-1H-indazol-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(2-methylquinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-aminoquinolin-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-ethyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-cyclobutyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-{[4-({4-[1-(oxetan-3-yl)-1H-indazol- 6-yl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(propan-2-yl)-1H-indazol- 6-yl]phenyl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(2-methoxyethyl)-1H- indazol-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(cyclopropylmethyl)-1H- indazol-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(1-propyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(cyclobutylmethyl)-1H- indazol-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(oxetan-3-ylmethyl)-1H- indazol-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-{[4-({4-[1-(2-hydroxyethyl)-1H- indazol-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol

1-[(4-{[4-(1-cyclopropyl-1H-indazol-6- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-N- methylcyclopropanecarboxamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-N- methylcyclobutanecarboxamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl}piperazin-1-yl)carbonyl)phenyl]phenyl}-N- methylcyclobutanesulfonamide

N-cyclopropyl-3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]-N- methylbenzene-1-sulfonamide

N-cyclopropyl-3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl}-N- methylbenzamide

2-cyclobutyl-N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}acetamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-1- methylazetidine-3-carboxamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-3- methyloxetane-3-carboxamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-2- (oxetan-3-yl)acetamide

3-fluoro-N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclobutane-1-carboxamide

3-ethyl-N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} oxetane-3-carboxamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl]carbonyl)phenyl}phenyl} propanamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-2- methylpropanamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} butanamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-2- methoxyacetamide

2-cyclopropyl-N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}acetamide

2,2-difluoro-N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}acetamide

N-{3-[4-([4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-1- methylcyclopropane-1-carboxamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclopentanecarboxamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclohexanecarboxamide

N-{3-[3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} oxane-4-carboxamide

1-cyclopropyl-N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} methanesulfonamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-2- methylpropane-1-sulfonamide

1,1-difluoro-N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} methanesulfonamide

3,3,3-trifluoro-N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}propane- 1-sulfonamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-1- methylcyclopropane-1-sulfonamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazine-1-yl}carbonyl)phenyl]phenyl} cyclobutanesulfonamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} oxolane-3-sulfonamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperain-1-yl}carbonyl)phenyl]phenyl} cyclopentanesulfonamide

2,2-difluoro-N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl)}carbonyl)phenyl]phenyl}ethane- 1-sulfonamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazine-1-yl}carbonyl)phenyl]phenyl}-2- methoxyethane-1-sulfonamide

1-cyclobutyl-N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} methanesulfonamide

2-hydroxy-N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} ethane-1-sulfonamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} oxane-4-sulfonamide

2-cyclopropyl-N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}ethane- 1-sulfonamide

3,3-difluoro-N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclobutane-1-carboxamide

1-[(4-{[4-(1H-1,3-benzodiazol-4-yl)-2-chlorophenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(2-cyclopropyl-2H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

1-[(4-{[4-(1-cyclopropyl-1H-indazol-5- yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol

N-{4-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclopropanecarboxamide

N-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-N- methylcyclopropanesulfonamide

N-{3-[4-({4-[(1- methoxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}-N- methylcyclopropanesulfonamide

3-cyclopropyl-1-{3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl}urea

3-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl-N- cyclopropylcarbamate

N-{4-[4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclopropanesulfonamide

N-{3-[3-chloro-4-({4-[(1- hydroxycyclopropyl)carbonyl]piperazin-1-yl}carbonyl)phenyl]phenyl} cyclopropanecarboxamide

N-(3-{4-[4-(1- hydroxyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl) cyclopentanecarboxamide

1-(4-{4-[4-(1H-pyrazol-4- yl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

l-{4-[4-(1,2,3,4-tetrahydroisoquinolin-2- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(1,3-dimethyl-1H-indazol-5-yl)-2- fluorobenzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1-(4-{4-[4-(1-methyl-1H-pyrazol-4- yl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

1-[(2S)-4-[2-fluoro-4-(1-methyl-1H-1,3- benzodiazol-5-yl)benzoyl]-2-methylpiperazine-1-carbonyl]cyclopropan- 1-ol

1-{4-[3-chloro-4-(1-methyl-1H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-{4-[3-chloro-4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-[4-(4-{pyrazolo[1,5-a]pyridin-6- yl}benzoyl)piperazine-1-carbonyl]cyclopropan-1-ol

l-{4-(4-(4-fluoro-2,3-dihydro-1H-indol-1- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

l-{4-[4-(3-methyl-1H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(3-methyl-1H-indazol-7- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(2S)-2-methyl-4-[4-(1-methyl-1H- indazol-6-yl)benzoyl]piperazine-1-carbonyl]cyclopropan-1-ol

1-{4-[3-chloro-4-(2-methyl-2H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

3,3,3-trifluoro-N-(3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)propane-1- sulfonamide

1-{4-[2-fluoro-4-(1-methyl-1H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{3,3-dimethyl-4-[4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

l-{4-[2,6-difluoro-4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-{4-(2-fluoro-4-(1-methyl-1H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1-amine

1-{4-[3-chloro-4-(6-chloro-1,3-benzoxazol- 2-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(1,3-dimethyl-1H-indazol-5-yl)-2- fluorobenzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

N-(3-{4-[4-(1- hydroxycyclopropanecarbonyl) piperazine-1-carbonyl]phenyl}phenyl) cyclobutanesulfonamide

1-{4-(4-(2,3-dihydro-1H-indol-1- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-(3-chloro-4-(1,3-dimethyl-1H-indazol- 5-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

l-[(2S)-2-methyl-4-[4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol

1-{4-[2,6-difluoro-4-(2-methyl-2H-indazol- 6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-(4-{4-[3-(5-amino-1,2-oxazol-3-yl)phenyl]-2-fluorobenzoyl}piperazine-1- carbonyl)cyclopropan-1-ol

1-[(2S)-2-methyl-4-[4-(2-methyl-2H- indazol-6-yl)benzoyl]piperazine-1-carbonyl]cyclopropan-1-ol

1-cyclobutyl-N-(3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl] phenyl}phenyl)methanesulfonamide

1-{4-[2-fluoro-4-(7-fluoro-1H-indazol-3- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(2S)-4-[4-(6-chloro-1,3-benzoxazol-2-yl)benzoyl]-2-methylpiperazine-1- carbonyl]cyclopropan-1-ol

1-{4-[4-(1H-indol-1-yl)benzoyl]piperazine- 1-carbonyl}cyclopropan-1-ol

1-{4-[4-(7-fluoro-1H-indazol-3- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(7-fluoro-1,2,3,4- tetrahydroisoquinolin-2-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(2-methyl-2H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(3-amino-1H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(3-amino-1,2-benzoxazol-5- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(1,3-dimethyl-1H-indazol-5-yl)-2- fluorobenzoyl]piperazine-1-carbonyl}cyclobutan-1-amine

1-{4-[2-fluoro-4-(3-methyl-1H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

ethyl N-(3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)carbamate

1-{4-[4-(5-chloro-2-methyl-1H-1,3-benzodiazol-7-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-[4-(4-{1H,2H,3H,4H,9H-pyrido[3,4- b]indol-2-yl}benzoyl)piperazine-1-carbonyl]cyclopropan-1-ol

1-[(2R,6S)-2,6-dimethyl-4-[4-(1-methyl-1H1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol

1-[4-(2-chloro-4-{3-chloroimidazo[1,2-a)pyridin-2-yl}benzoyl)piperazine-1- carbonyl]cyclopropan-1-ol

1-{4-[4-(4-chloro-2-fluorophenyl)benzoyl]- 3,3-dimethylpiperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-chloro-4-(1-methyl-1H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(2S)-4-[4-(4-chloro-2- fluorophenyl)benzoyl]-2-methylpiperazine-1-carbonyl]cyclopropan-1-ol

1-[(2S)-4-[4-(1,3-dimethyl-1H-indazol-5-yl)benzoyl]-2-methylpiperazine-1- carbonyl]cyclopropan-1-ol

1-(4-{4-[3-(5-amino-1,2-oxazol-3- yl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

2-(3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)acetonitrile

N-(3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl) cyclopentanesulfonamide

1-[(3S)-3-methyl-4-[4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol

1-cyclopropyl-N-(3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl) methanesulfonamide

1-{4-[3-chloro-4-(6-fluoro-1,3-benzoxazol- 2-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-(2-chloro-4-(2-methyl-2H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cydopropan-1-ol

1-{4-[2,6-difluoro-4-(1-methyl-1H-indazol- 6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(3R)-3-methyl-4-[4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol

N-(6-{4-[4-(1- hydroxycyclopropanecarbonyl(piperazine-1-carbonyl]phenyl}-1,2-benzoxazol-3- yl)cyclopropanecarboxamide

1-[(3R,5S)-3,5-dimethyl-4-[4-(1-methyl-1H1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol

propan-2-yl N-(3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)carbamate

1-{4-[4-(3-amino-1H-indazol-5- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(2R)-2-methyl-4-[4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol

3,3-difluoro-N-(3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclobutane-1- carboxamide

1-[(2S/6R)-4-[4-(6-fluoro-1,3-benzoxazol-2-yl)benzoyl]-2,6-dimethylpiperazine-1- carbonyl]cyclopropan-1-ol

1-(4-{4-[1-(2-hydroxyethyl)-1H-1,3-benzodiazol-6-yl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol

1-{4-[4-(1H-1,3-benzodiazol-4-yl)-2- chlorobenzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(5-fluoro-2,3-dihydro-1H-indol-1- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[4-(4-{3-chloroimidazo[1,2-a]pyridin-2-yl}-2-fluorobenzoyl)piperazine-1- carbonyl]cyclopropan-1-ol

1-{4-[4-(4-chloro-2-fluorophenyl)-2- fluorobenzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[3-chloro-4-(4-chloro-2- fluorophenyl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-chloro-4-(6-chloro-1,3-benzoxazol- 2-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(5-fluoro-2,3-dihydro-1H-isoindol- 2-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(3-methyl-1H-indazol-4- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(6-methoxy-1,3-benzoxazol-2- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(3-methyl-1H-indazol-7- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(2R)-4-[4-(4-chloro-2- fluorophenyl)benzoyl]-2-methylpiperazine-1-carbonyl]cyclopropan-1-ol

1-(3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclobutane-1- carbonitrile

1-{4-[2-fluoro-4-(6-fluoro-1,3-benzoxazol- 2-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[4-(4-{1H,2H,3H,4H,5H-pyrido[4,3- b]indol-2-yl}benzoyl)piperazine-1-carbonyl]cyclopropan-1-ol

1-{4-[4-(2-methyl-1H-indol-1- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(2S)-2-methyl-4-[4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-amine

1-{4-[3-fluoro-4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl}cyclobutan-1-amine

1-{4-[3-fluoro-4-(1-methyl-1H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(2S)-4-[4-(6-fluoro-1,3-benzoxazol-2-yl)benzoyl]-2-methylpiperazine-1- carbonyl]cyclopropan-1-ol

1-{4-[4-(4-fluoro-2,3-dihydro-1H-isoindol- 2-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-(4-{3-chloro-4-[3- (cyclopropanesulfonyl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

1-{4-[4-(7-fluoro-2,3-dihydro-1H-indol-1- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(3-cyclopropyl-1H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(6-fluoro-1,3-benzoxazol-2-yl)benzoyl]-3,3-dimethylpiperazine-1- carbonyl}cyclopropan-1-ol

1-{4-[4-(3-methyl-1H-indazol-1- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(3-methyl-1H-indazol-7- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1-{4-[4-(1-methanesulfonyl-1H-indol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(1-methyl-1H-1,3-benzodiazol-5- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1-{4-[4-(2-methyl-2,3-dihydro-1H-indol-1-yl)benzoyl]piperazine-1-carbonyl} cyclopropan-1-ol

1-{4-[4-(5-fluoro-1H-1,2,3-benzotriazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[3-chloro-4-(5-chloro-2- fluorophenyl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

l-[(2S,6R)-4-[4-(4-chloro-2- fluorophenyl)benzoyl]-2,6-dimethylpiperazine-1- carbonyl]cyclopropan-1-ol

N-(3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)oxane-4- sulfonamide

1-{4-[4-(1-methyl-1H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1-{4-[4-(7-methoxy-1,2,3,4- tetrahydroisoquinolin-2-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-(3-{3-fluoro-4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclopropane-1- carbonitrile

1-{4-[2-fluoro-4-(2-methyl-1H-indol-1- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(1H-1,3-benzodiazol-1- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-(3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclopropane-1- carbonitrile

1-{4-[2-fluoro-4-(3-methyl-1H-indazol-1- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(1-methyl-1H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

2-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-1,2,3,4- tetrahydroisoquinoline-7-carbonitrile

1-(4-{4-[1-(2-hydroxyethyl)-1H-1,3-benzodiazol-5-yl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol

1-[(2R)-4-[4-(6-fluoro-1,3-benzoxazol-2-yl)benzoyl]-2-methylpiperazine-1- carbonyl]cyclopropan-1-ol

1-{4-[4-(1H-indazol-1- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-chloro-4-(5-chloro-2- fluorophenyl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(1,3-dimethyl-1H-indazol-5-yl)-3- fluorobenzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(4-chloro-2-fluorophenyl)benzoyl]- 4,7-diazaspiro[2.5]octane-7-carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(7-fluoro-1H-indazol-3- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

6-{1-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]piperidin-4-yl}naphthalene-2- carbonitrile

1-(3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)imidazolidin-2- one

1-{4-[2,6-difluoro-4-(2-methyl-2H-indazol- 6-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1,3-dimethyl-5-{4-[4-(oxetane-2- carbonyl)piperazine-1-carbonyl]phenyl}-1H-indazole

1-{4-[2-fluoro-4-(2-methyl-2H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1-(4-{4-[3-(5-amino-1H-1,2,4-triazol-3- yl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

l-{4-[4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]-4,7-diazaspiro[2.5]octane-7- carbonyl}cyclopropan-1-ol

1-{4-[4-(2-methyl-1H-indol-3- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(2-methyl-1H-1,3-benzodiazol-5- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(6-fluoro-1,3-benzoxazol-2-yl)benzoyl]-4,7-diazaspiro[2.5]octane-7- carbonyl}cyclopropan-1-ol

1-{4-[4-(6-fluoro-1-methyl-1H-1,2,3-benzotriazol-5-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-{4-[4-(1-methyl-1H-1,3-benzodiazol-5- yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1-ol

6-chloro-4-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-2,3-dihydro-1H-1,3- benzodiazol-2-one

1-(4-{4-[2-(hydroxymethyl)-1H-1,3- benzodiazol5-yl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol

5-{4-[4-(1- aminocyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-1,2-benzoxazol-3-amine

1-{4-[4-(2-cyclopropyl-2H-indazol-5- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-{4-[4-(3-methyl-1,2,3,4- tetrahydroisoquinolin-2-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol

1-{4-[4-(2,3-dihydro-1H-isoindol-2- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(3R)-4-[4-(4-chloro-2- fluorophenyl)benzoyl]-3-methylpiperazine-1-carbonyl]cyclopropan-1-ol

1-[4-(4-{3-methyl-1H-pyrazolo[3,4- b]pyridin-5-yl}benzoyl)piperazine-1-carbonyl]cyclopropan-1-ol

l-{4-[4-(3-methyl-1H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1-{4-[2-fluoro-4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-amine

6-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-1-methyl-1H-indazol- 3-ol

1-{4-[4-(1,2,3,4-tetrahydroquinolin-1- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(3-methyl-1H-indazol-7- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1-[4-(4-{4H,5H,6H,7H-thieno[3,2-c] pyridin-5-yl}benzoyl)piperazine-1-carbonyl]cyclopropan-1-ol

1-{4-[4-(1-methyl-1H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1-amine

1-(4-{4-[3-(2-amino-1,3-thiazol-4- yl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

1-{4-[4-(1,3-dimethyl-1H-indazol-5- yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1-amine

1-(4-{4-[3-(cyclopropanesulfonyl)phenyl]- 2-fluorobenzoyl}piperazine-1-carbonyl(cyclopropan-1-ol

1-{4-[4-(6-fluoroquinazolin-2- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

N-(5-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-1,2-benzoxazol-3- yl)cyclopropanecarboxamide

4-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-1-methyl-2,3-dihydro- 1H-indol-2-one

1-[(3R)-4-[4-(6-fluoro-1,3-benzoxazol-2-yl)benzoyl]-3-methylpiperazine-1- carbonyl]cyclopropan-1-ol

1-{4-[4-(2-methyl-1H-1,3-benzodiazol-1- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(5-chloro-2- fluorophenyl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1-{4-[3-fluoro-4-(2-methyl-2H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-N-methylbenzamide

1-(4-{4-[3-(5-amino-1H-pyrazol-3- yl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

1-[(2S)-2-methyl-4-[4-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)benzoyl]piperazine- 1-carbonyl]cyclopropan-1-ol

1-[(3S)-4-[4-(4-chloro-2- fluorophenyl)benzoyl]-3-methylpiperazine-1-carbonyl]cyclopropan-1-ol

2-(3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenoxy)-N- methylacetamide

1-{4-[4-(1-cyclopropyl-1H-indazol-5- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-methyl-5-{4-[4-(oxetane-2- carbonyl)piperazine-1-carbonyl]phenyl}-1H-1,3-benzodiazole

(1-{4-[4-(1-methyl-1H-1,3-benzodiazol-5- yl)benzoyl]piperazine-1-carbonyl}cyclopropyl)methanol

1-{4-[4-(1-methyl-1H-1,3-benzodiazol-5- yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1-amine

1-[4-(3-chloro-4-{3-chloroimidazo[1,2-a]pyridin-2-yl}benzoyl)piperazine-1- carbonyl]cyclopropan-1-ol

1-[(2R)-2-(hydroxymethyl)-4-[4-(1-methyl- 1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol

1-{4-[4-(2,3,4,5-tetrahydro-1H-3- benzazepin-3-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(2S,6R)-4-[4-(6-fluoro-1,3-benzoxazol-2-yl)benzoyl]-2,6-dimethylpiperazine-1- carbonyl]cyclopropan-1-amine

1-(2S)-4-[4-(6-fluoro-1,3-benzoxazol-2-yl)benzoyl]-2-methylpiperazine-1- carbonyl]cyclopropan-1-amine

1-(4-{4-[3-(5-methyl-1,3,4-thiadiazol-2- yl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

1-{4-[4-(3-methyl-2H-indazol-2- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

2-(3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)-2- methylpropanenitrile

1-[(2S)-4-{4-[3- (cyclopropanesulfonyl)phenyl]benzoyl}-2-methylpiperazine-1-carbonyl] cyclopropan-1-ol

1-(3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)pyrrolidin-2- one

3-(3-{4-[4-(1- aminocyclopropanecarbonyl)piperazine-1-carbonyl]-3-fluorophenyl}phenyl)-1,2- oxazol-5-amine

6-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine- 1-carbonyl]phenyl}-Nmethylpyridine-2- carboxamide

1-[(3S)-4-[4-(6-fluoro-1,3-benzoxazol-2-yl)benzoyl]-3-methylpiperazine-1- carbonyl]cyclopropan-1-ol

4-(3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)oxane-4- carbonitrile

1-(4-{4-[3-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl]benzoyl}piperazine-1-carbonyl)cyclopropan-1-ol

5-{3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)-5- methylimidazolidine-2,4-dione

1-{4-[2-fluoro-4-(2-methyl-1H-indol-1- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-amine

1-{4-[4-(3-amino-1,2-benzoxazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[2-fluoro-4-(2-methyl-2H-indazol-6- yl)benzoyl]piperazine-1-carbonyl}cyclobutan-1-amine

2-(3-{4-[4-(1- hydroxycyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)-1λ⁶,2- thiazolidine-1,1-dione

1-{4-[4-(6-chloro-1,3-benzoxazol-2-yl)-3- fluorobenzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(2,3,4,5-tetrahydro-1H-2- benzazepin-2 yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[4-(4-{3-chloroimidazo[1,2-a]pyridin-2-yl}-3-fluorobenzoyl)piperazine-1- carbonyl]cyclopropan-1-ol

1-(3-{4-[4-(1- aminocyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}phenyl)cyclopropane-1- carbonitrile

1-{4-[3-fluoro-4-(6-fluoro-1,3-benzoxazol- 2-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-{4-[4-(2-methyl-2H-1,2,3-benzotriazol-5- yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol

1-[(3S)-3-methyl-4-[4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-amine

-   -   38. A pharmaceutical composition comprising therapeutically        effective amounts of at least one compound of embodiment 2, or a        pharmaceutically acceptable salt thereof, and at least one        pharmaceutically acceptable carrier.    -   39. A method of inhibiting Fatty Acid Synthase (“FASN”) in a        patient by administering therapeutically effective amounts of at        least one compound of embodiment 2, or a pharmaceutically        acceptable salt thereof.    -   40. A method of inhibiting FASN in a patient by administering        therapeutically effective amounts of the pharmaceutical        composition of embodiment 38.    -   41. A method of treating, preventing, inhibiting or eliminating        a disease or condition in a patient by inhibiting FASN in said        patient by administering therapeutically effectives amount of at        least one compound of embodiment 2, or a pharmaceutically        acceptable salt thereof, wherein said disease or condition is        selected from the group consisting of cancer, ovarian cancer,        breast cancer, uterine cancer, colon cancer, cervical cancer,        lung cancer, prostate cancer, skin cancer, bladder cancer,        pancreatic cancer, leukemia, lymphoma, Hodgkin's disease, viral        infections, Human Immunodeficiency Virus, hepatitis virus,        herpes virus, herpes simplex, inflammatory disorders, irritable        bowel syndrome, inflammatory bowel disease, rheumatoid        arthritis, asthma, chronic obstructive pulmonary disease,        osteoarthritis, osteoporosis, dermatitis, atoptic dermatitis,        psoriasis, systemic lupus erythematosis, multiple sclerosis,        psoriatic arthritis, ankylosing spodylitis, graft-versus-host        disease, cerebrovascular accident, atherosclerosis,        glomerulonephiritis, metabolic syndrome, non-small cell lung        cancer, small cell lung cancer, multiple myeloma, leukemias,        lymphomas, squamous cell cancers, kidney cancer, uretral and        bladder cancers, cancers of head and neck, cancers of the brain        and central nervous system, obesity, viral infections, and        diabetes.    -   42. A method of treating a disease or condition in a patient by        inhibiting FASN in said patient by administering therapeutically        effectives amounts of the composition of embodiment 38, wherein        said disease or condition is selected from the group consisting        of cancer, ovarian cancer, breast cancer, uterine cancer, colon        cancer, cervical cancer, lung cancer, prostate cancer, skin        cancer, bladder cancer, pancreatic cancer, leukemia, lymphoma,        Hodgkin's disease, viral infections, Human Immunodeficiency        Virus, hepatitis virus, herpes virus, herpes simplex,        inflammatory disorders, irritable bowel syndrome, inflammatory        bowel disease, rheumatoid arthritis, asthma, chronic obstructive        pulmonary disease, osteoarthritis, osteoporosis, dermatitis,        atoptic dermatitis, psoriasis, systemic lupus erythematosis,        multiple sclerosis, psoriatic arthritis, ankylosing spodylitis,        graft-versus-host disease, Alzheimer's disease, cerebrovascular        accident, atherosclerosis, glomerulonephiritis, metabolic        syndrome, non-small cell lung cancer, small cell lung cancer,        multiple myeloma, leukemias, lymphomas, squamous cell cancers,        kidney cancer, uretral and bladder cancers, cancers of head and        neck, cancers of the brain and central nervous system, obesity,        viral infections, and diabetes.    -   43. The method of embodiment 42, wherein said disease is a        cancer.    -   44. The method of embodiment 43, wherein said cancer is selected        from the group consisting of leukemia, lymphoma, ovarian cancer,        breast cancer, uterine cancer, colon cancer, cervical cancer,        lung cancer, prostate cancer, skin cancer, CNS cancer, bladder        cancer, pancreatic cancer and Hodgkin's disease.    -   45. The method of embodiment 42, wherein said disease is a viral        infection.    -   46. The method of embodiment 42, wherein said disease is        obesity.    -   47. The method of embodiment 42, wherein said disease is        diabetes.    -   48. The pharmaceutical composition of embodiment 38, further        comprising therapeutically effective amounts of one or more        additional therapeutic agents.    -   49. The pharmaceutical composition of embodiment 48, wherein        said one or more additional therapeutic agents are selected from        the group consisting of cytotoxic agent, cisplatin, doxorubicin,        taxotere, taxol, etoposide, irinotecan, camptostar, topotecan,        paclitaxel, docetaxel, the epothilones, tamoxifen,        5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide,        SCH 66336, tipifarnib (Zarnestra®), R115777, L778,123, BMS        214662, Iressa®, Tarceva®, C225, GLEEVEC®, Intron®, Peg-Intron®,        aromatase combinations, ara-C, adriamycin, cytoxan, gemcitabine,        Uracil mustard, Chlormethine, Ifosfamide, Melphalan,        Chlorambucil, Pipobroman, Triethylenemelamine,        Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,        Streptozocin, Dacarbazine, Floxuridine, Cytarabine,        6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate,        leucovirin, oxaliplatin (ELOXATIN®), Pentostatine, Vinblastine,        Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin,        Epirubicin, Idarubicin, Mithramycin™, Deoxycoformycin,        Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol,        Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone,        Dromostanolone propionate, Testolactone, Megestrol acetate,        Methylprednisolone, Methyltestosterone, Prednisolone,        Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,        Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate,        Leuprolide, Flutamide, Toremifene, goserelin, Carboplatin,        Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone,        Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine,        Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin,        Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine,        Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan,        Trastuzumab, Lerozole, Fulvestrant, Exemestane, Rituximab, C225,        Campath, leucovorin, dexamethasone, bicalutamide, carboplatin,        chlorambucil, cisplatin, letrozole, and megestrol, valrubicin,    -   50. A pharmaceutical composition comprising therapeutically        effective amounts of at least one compound of embodiment 37, or        a pharmaceutically acceptable salt thereof, and at least one        pharmaceutically acceptable carrier.    -   51. A method of inhibiting Fatty Acid Synthase (“FASN”) in a        patient by administering therapeutically effective amounts of at        least one compound of embodiment 37, or a pharmaceutically        acceptable salt thereof.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand other variations thereof will be apparent to those of ordinary skillin the art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

What is claimed is:
 1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein R₁ is

A and B are each independently O; L is

wherein m is 2, n is 1, and R_(b) is C₁-C₄ alkyl; Ar₁ is a 6-membermonocyclic aryl or 6-member monocyclic heteroaryl comprising 1 or 2heteroatoms that are N, wherein said aryl or heteroaryl is eitherunsubstituted or optionally independently substituted with 1 or moresubstituents which can be the same or different and are independentlyselected from the group consisting of halogen, alkyl, and -alkoxy; andR₂ is a substituted or unsubstituted 8-10 membered fused polycyclic arylor heteroaryl, wherein R₂ is optionally substituted with 1 or moresubstituents which can be the same or different and are independentlyselected from the group consisting of halogen, alkyl and -alkoxy.
 2. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Ar₁ is

wherein Ph₁ is selected from the group consisting of phenyl, pyridinyl,pyrazinyl and pyrimidinyl; and R_(e) is selected from the groupconsisting of hydrogen, halogen and C₁-C₃ alkyl.
 3. The compound ofclaim 2, or a pharmaceutically acceptable salt thereof, wherein Ph₁ isphenyl.
 4. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein Ar₁ is

wherein R_(e) is selected from the group consisting of hydrogen, halogenand C₁-C₃ alkyl.
 5. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R_(b) is methyl.
 6. The compound ofclaim 4, or a pharmaceutically acceptable salt thereof, wherein R_(b) ismethyl.
 7. The compound of claim 6, or a pharmaceutically acceptablesalt thereof, wherein R_(e) is hydrogen.
 8. The compound of claim 6, ora pharmaceutically acceptable salt thereof, wherein R_(e) is halogen. 9.The compound of claim 8, or a pharmaceutically acceptable salt thereof,wherein Ar₁ is


10. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R₂ is a substituted or unsubstituted 9-membered 6,5bicyclic heteroaryl and said heteroaryl has 1, 2, 3, or 4 heteroatomsand said heteroatoms are independently O, S, or N.
 11. The compound ofclaim 2, or a pharmaceutically acceptable salt thereof, wherein R₂ is asubstituted or unsubstituted 9-membered 6,5 bicyclic heteroaryl and saidheteroaryl has 1, 2, 3, or 4 heteroatoms and said heteroatoms areindependently O, S, or N.
 12. The compound of claim 3, or apharmaceutically acceptable salt thereof, wherein R₂ is a substituted orunsubstituted 9-membered 6,5 bicyclic heteroaryl and said heteroaryl has1, 2, 3, or 4 heteroatoms and said heteroatoms are independently O, S,or N.
 13. The compound of claim 5, or a pharmaceutically acceptable saltthereof, wherein R₂ is a substituted or unsubstituted 9-membered 6,5bicyclic heteroaryl and said heteroaryl has 1, 2, 3, or 4 heteroatomsand said heteroatoms are independently O, S, or N.
 14. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R₂ isselected from the group consisting of:


15. The compound of claim 2, or a pharmaceutically acceptable saltthereof, wherein R₂ is selected from the group consisting of:


16. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein R is

A and B are each independently O; L is

substituted with one or more R_(b), wherein R_(b) is methyl; Ar₁ is

R_(e) is selected from the group consisting of hydrogen, and halogen;and R₂ is a substituted or unsubstituted 9-membered 6,5 bicyclicheteroaryl and said heteroaryl has 1, 2, 3, or 4 heteroatoms and saidheteroatoms are independently O, S, or N, wherein R₂ is optionallysubstituted with 1 or more substituents which can be the same ordifferent and are independently selected from the group consisting ofhalogen, alkyl and -alkoxy.
 17. The compound of claim 16, or apharmaceutically acceptable salt thereof, wherein R₂ is selected fromthe group consisting of:


18. The compound of claim 16, or a pharmaceutically acceptable saltthereof, wherein R₂ is selected from the group consisting of:


19. The compound of claim 16, or a pharmaceutically acceptable saltthereof, wherein L is selected from the group consisting of:


20. The compound of claim 18, or a pharmaceutically acceptable saltthereof, wherein L is selected from the group consisting of:


21. The compound of claim 16, selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 22. A compound of Formula(I)

or a pharmaceutically acceptable salt thereof, wherein R₁ is

A and B are each independently O; L is selected from the groupconsisting of:

Ar₁ is

R_(e) is selected from the group consisting of hydrogen, and halogen;and R₂ is selected from the group consisting of:


23. The compound of claim 22, or a pharmaceutically acceptable saltthereof, wherein R_(e) is hydrogen.
 24. The compound of claim 21, havingthe formula:

or a pharmaceutically acceptable salt thereof.
 25. The compound of claim21, having the formula:

or a pharmaceutically acceptable salt thereof.
 26. The compound of claim21, having the formula:

or a pharmaceutically acceptable salt thereof.
 27. The compound of claim21, having the formula:

or a pharmaceutically acceptable salt thereof.